Substituted 2-(Pyrrolidine-3-yl)acetic Acid Derivative, Preparation Method and Use Thereof

Abstract

The invention provides a class of compounds represented by Formula (I), and pharmaceutically acceptable salts thereof. The compounds of the invention have strong inhibitory activity against Lp(a) assembly and can be used to treat cardiovascular diseases (CVDs).

Description

US_SUMMARY_OF_INVENTIONCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is based on and claims priority to Chinese Patent Application Nos. 202311536343.5 filed on Nov. 17, 2023; 202410174573.X filed Feb. 7, 2024; 202410811526.1 filed on Jun. 21, 2024; and 202411250214.4 filed on Sep. 6, 2024, the entire contents of all which are hereby incorporated by reference.TECHNICAL FIELD

[0002] The invention relates to the field of pharmaceutical technology, and in particular, to compounds as Lp(a) inhibitors, particularly a substituted 2-(pyrrolidine-3-yl) acetic acid derivative and its preparation method and usage.BACKGROUND TECHNOLOGY

[0003] Lipoprotein (a) (Lp(a)) is a lipoprotein particle synthesized in the liver, consisting of cholesterol-rich low-density lipoprotein (LDL-C)-like particles attached to apolipoprotein (a). Lp(a) levels are primarily genetically determined, vary widely across populations, and are largely unaffected by lifestyle interventions.

[0004] Lp(a) is associated with an increased risk of coronary artery diseases, ischemic stroke, aortic stenosis, heart failure, atrial fibrillation, and peripheral artery diseases. Elevated Lp(a) levels (≥30 mg / dL) are present in approximately 20% of people. The increased risk of cardiovascular diseases (CVDs) associated with Lp(a) is mainly attributed to the dual prothrombotic effects of Apo (a) [Apo (a) structure is similar to plasminogen], as well as the atherogenic effects of Apo B (apolipoprotein B) and the pro-inflammatory effects of oxidized phospholipids (OxPL). Lp(a) is not only a causative factor for atherosclerotic cardiovascular disease (ASCVD) but also for calcific aortic valve disease. Elevated Lp(a) plasma levels are an independent risk factor for CVDs.

[0005] There are few approved treatment options for patients with elevated Lp(a) concentration. Plasmapheresis can be used to filter the blood to remove LDL and Lp(a); however, the effect is temporary and usually needs to be repeated every two weeks, and patient compliance is not very good. To date, there are no approved drug therapies for lowering Lp(a) levels. Therefore, there is a great need to provide patients with CVDs with usable compounds and treatment options to lowering plasma Lp(a) levels.Content of the Invention

[0006] The purpose of the invention is to provide a class of novel compounds for lowering plasma Lp(a) levels, a method for preparing the compounds, and their usage in the treatment of diseases mediated by Lp(a). The novel compounds are biochemically effective and physiologically active.

[0007] Firstly, the invention provides a compound represented by the following Formula (I), or a pharmaceutically acceptable salt thereof:

[0008] In the formula, is a single bond or a double bond;

[0009] A is CRX, P, P(O), N, C6-12 aryl, 5-14 membered heteroaryl, C3-8carbocyclyl or 5-18 membered heterocyclyl; wherein the aryl, heteroaryl, carbocyclyl and heterocyclyl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, C1-3alkyl, and C1-3alkoxy;

[0010] when is a single bond, RX is H, —OH, or C1-3alkoxy;

[0011] when is a double bond, RX does not exist;

[0012] L1 is selected from —C1-3alkylene-C6-10aryl-C6-10aryl-C1-3alkylene-, —C1-3alkylene-C6-10aryl-5-12 membered heteroaryl-C1-3alkylene-, —C1-3alkylene-5-12 membered heteroaryl-5-12 membered heteroaryl-C1-3alkylene-, andwherein the C1-3alkylene is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; wherein the aryl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, and C1-3alkoxy; * is the connecting end of L1 and A;L2 is selected from —C1-3alkylene-C6-10aryl-C6-10aryl-C1-3alkylene-, —C1-3alkylene-C6-10aryl-5-12 membered heteroaryl-C1-3alkylene-, —C1-3alkylene-5-12 membered heteroaryl-5-12 membered heteroaryl-C1-3alkylene-, andwherein the C1-3alkylene is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; wherein the aryl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, and C1-3alkoxy; * is the connecting end of L2 and A;R is selected from H, —C1-3alkylene-C6-10aryl, —C1-3alkylene-5-12 membered heteroaryl, C1-6alkyl, andwherein the C1-3alkylene is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; wherein the aryl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, C1-3alkoxy, and C1-3aminoalkyl; wherein the C1-6alkyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, carboxyl, —CN, —OH, —NH2, C1-3alkyl, and C1-3alkoxy; * is the connecting end of R and A; L3 is selected from —C1-6alkylene-, —C2-6alkenylene-, —C2-6alkynylene-, —C1-3alkylene-C6-10aryl-C6-10aryl-C1-3alkylene-, —C1-3alkylene-C6-10aryl-5-12 membered heteroaryl-C1-3alkylene-, —C1-3alkylene-5-12 membered heteroaryl-C6-10aryl-C1-3alkylene-, —C1-3alkylene-5-12 membered heteroaryl-5-12 membered heteroaryl-C1-3alkylene-, andwherein the alkylene, alkenylene, and alkynylene are optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; wherein the aryl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, C1-3alkyl, and C1-3alkoxy; * is the connecting end of L3 and A;each of rings W1, W2, and W3 is independently selected from C6-12aryl, 5-12 membered heteroaryl, C6-14cycloalkyl, and 5-12 membered heterocyclyl; wherein the aryl, heteroaryl, cycloalkyl, and heterocyclyl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, —OH, —NH2, —CHO, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, C1-3haloalkoxy, —N(C1-3alkyl)2, —NH(C1-3alkyl), and —C(O)C1-3alkyl;each of Z11, Z12, Z21, Z22, Z31, and Z32 is independently selected from a bond, —O—, —S—, —NH—, —Se—, —C1-4alkylene-, —C1-8oxaalkylene-, —C1-4thiaalkylene-, —C1-4azaalkylene-, and —C1-4selenaalkylene-; wherein the alkylene, oxaalkylene, thiaalkylene, azaalkylene, and selenaalkylene are optionally substituted by one or more substituents independently selected from Z41; Z41 is independently selected from deuterium, halogen, oxo, thio, —CN, —OH, —NH2, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, and C1-3haloalkoxy; or any two Z41 together with the atom to which they are attached form C3-6cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl;each of R31, R32, and R33 is independently selected from hydrogen, deuterium, halogen, C1-6alkyl, C1-6haloalkyl, C1-6deuteroalkyl, C1-6alkoxy, C1-6haloalkoxy, and C1-6deuteroalkoxy;each of h1, h2, h3, h4, h5, and h6 is independently 0, 1, or 2;each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R41, R42, R43, R44, R45, R46, R47, R48, and R49 is independently selected from H, deuterium, —CN, —OH, —NH2, halogen, C1-6alkyl, C1-6haloalkyl, C1-6 alkoxy, C1-6haloalkoxy, —N(C1-3alkyl)2, and —NH(C1-3alkyl);each of R50, R51, R52 is independently selected from H, deuterium, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, —C1-3alkylene-O—C1-6alkyl, —C1-3alkylene-O—C(O)—C1-6alkyl, the alkyl, alkenyl, alkoxy, and alkylene are optionally substituted by one or more substituents independently selected from deuterium, halogen, —OH, —NH2, —CN, oxo, C1-3alkyl, and C1-3alkoxy;provided that when A is N, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R41, R42, R43, R44, R45, R46, R47, R48, and R49 are all H, L1, L2, and L3 are notat the same time;provided that when A is N, R isand R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R41, and R42 are all H, L1 and L2 are notat the same time, * is the connecting end of R and A;provided that the compound is notthe heteroatom in the heterocyclyl or heteroaryl is independently selected from O, N, or S, and the number of heteroatoms is 1, 2, 3, or 4.In an embodiment for the compound represented by the above formula (I), R is a group containing L3; L1, L2 and L3 are groups containing Z11, Z21 and Z31 respectively, and one and only one of Z11, Z21 and Z31 is a group containing a double bond; the double bond is, for example, a double bond between C and O in —C(O)—, or a double bond between C and S in —C(S)—; further preferably, Z11, Z21 and Z31 are different from each other, or two groups not containing the double bond in Z11, Z21 and Z31 are the same and the two same groups contain —O—, —NH—, —S—, or —Se—, preferably, —O—; still further preferably, Z11, Z21 and Z31 each independently have a molecular weight of 14.0-107.1, preferably 14.0-60; preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60; still more preferably, Z11, Z21 and Z31 are selected from —CH2—, —CD2—, —CH2CH2—, —CD2CH2—, —C(O)—, —CH2C(O)—, —NHC(O)—, —OC(O)—, —CH2CH2O—, —OCH2C(O)—, —CH2OC(O)—, —CH2CH2CH2O—, and —S—C(O)—.In some embodiments, a compound represented by the following Formula (I-1-P1), or a pharmaceutically acceptable salt thereof is provided:wherein, is a single bond or a double bond;A is CRX, P, P(O) or N;when is a single bond; RX is H, —OH, or C1-3alkoxy;when is a double bond, RX does not exist;L1 is selected from —C1-3alkylene-C6-10aryl-C6-10aryl-C1-3alkylene-, —C1-3alkylene-C6-10aryl-5-12 membered heteroaryl-C1-3alkylene-, —C1-3 alkylene-5-12 membered heteroaryl-5-12 membered heteroaryl-C1-3alkylene-, andwherein the C1-3alkylene is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; wherein the aryl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, and C1-3alkoxy; * is the connecting end of L1 and A;L2 is selected from —C1-3alkylene-C6-10aryl-C6-10aryl-C1-3alkylene-, —C1-3alkylene-C6-10aryl-5-12 membered heteroaryl-C1-3alkylene-, —C1-3alkylene-5-12 membered heteroaryl-5-12 membered heteroaryl-C1-3alkylene-, andwherein the C1-3alkylene is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; wherein the aryl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, and C1-3alkoxy; * is the connecting end of L2 and A;R is selected from H, —C1-3alkylene-C6-10aryl, —C1-3alkylene-5-12 membered heteroaryl, C1-6alkyl, andwherein the C1-3alkylene is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; wherein the aryl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, C1-3alkoxy, and C1-3aminoalkyl; wherein the C1-6alkyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, carboxyl, —CN, —OH, —NH2, C1-3alkyl, and C1-3alkoxy; * is the connecting end of R and A;L3 is selected from —C1-6alkylene-, —C2-6alkenylene-, —C2-6alkynylene-, —C1-3alkylene-C6-10aryl-C6-10aryl-C1-3alkylene-, —C1-3alkylene-C6-10aryl-5-12 membered heteroaryl-C1-3alkylene-, —C1-3alkylene-5-12 membered heteroaryl-C6-10aryl-C1-3alkylene-, —C1-3alkylene-5-12 membered heteroaryl-5-12 membered herteoaryl-C1-3alkylene-, andwherein the alkylene, alkenylene, and alkynylene are optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; wherein the aryl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, C1-3alkyl, and C1-3alkoxy; * is the connecting end of L3 and A;each of rings W1, W2, and W3 is independently selected from C6-12aryl, 5-12 membered heteroaryl, C6-14cycloalkyl, and 5-12 membered heterocyclyl; wherein the aryl, heteroaryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more substituents independently selected from deuterium, halogen, —CN, C1-3alkyl, and C1-3alkoxy;each of Z11, Z12, Z21, Z22, Z31, and Z32 is independently selected from a bond, —C1-4alkylene-, and —C1-4oxaalkylene-; wherein the alkylene and oxaalkylene are optionally substituted with one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, C1-3alkyl, and C1-3alkoxy;each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 is independently selected from H and deuterium;provided that when A is N, L1, L2, and L3 are notat the same time;provided that when A is N and R isL1 and L2 are notat the same time, and * is the end connecting of R and A;the heteroatom in the heterocyclyl or heteroaryl is independently selected from O, N, or S, and the number of heteroatoms is 1, 2, or 3.In an embodiment for the compound represented by the above formula (I-1-P1), R is a group containing L3; L1, L2 and L3 are groups containing Z11, Z21 and Z31 respectively, and one and only one of Z11, Z21 and Z31 is a group containing a double bond; the double bond is, for example, a double bond between C and O in —C(O)—, or a double bond between C and S in —C(S)—; further preferably, Z11, Z21 and Z31 are different from each other, or two groups not containing the double bond in Z11, Z21 and Z31 are the same and the two same groups contain —O—, —NH—, —S—, or —Se—, preferably, —O—; still further preferably, Z11, Z21 and Z31 each independently have a molecular weight of 14.0-107.1, preferably 14.0-60; preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60; still more preferably, Z11, Z21 and Z31 are selected from —CH2—, —CD2—, —CH2CH2—, —CD2CH2—, —C(O)—, —CH2C(O)—, —NHC(O)—, —OC(O)—, —CH2CH2O—, —OCH2C(O)—, —CH2OC(O)—, —CH2CH2CH2O—, and —S—C(O)—.In some embodiments, a compound represented by the following Formula (I-1-P2), or a pharmaceutically acceptable salt thereof is provided:wherein, is a single bond or a double bond;A is CRX, P, P (O) or N;when is a single bond, RX is H, —OH, C1-3alkoxy;when is a double bond, RX does not exist;L1 is selected from —C1-3alkylene-C6-10aryl-C6-10aryl-C1-3alkylene-, —C1-3alkylene-C6-10aryl-5-12 membered heteroaryl-C1-3alkylene-, —C1-3alkylene-5-12 membered heteroaryl-5-12 membered heteroaryl-C1-3alkylene-,wherein the C1-3alkylene is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; wherein the aryl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, and C1-3alkoxy; * is the connecting end of L1 and A;L2 is selected from —C1-3alkylene-C6-10aryl-C6-10aryl-C1-3alkylene-, —C1-3alkylene-C6-10aryl-5-12 membered heteroaryl-C1-3alkylene-, —C1-3alkylene-5-12 membered heteroaryl-5-12 membered heteroaryl-C1-3alkylene-,wherein the C1-3alkylene is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; wherein the aryl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, and C1-3alkoxy; * is the connecting end of L2 and A;R is selected from H, —C1-3alkylene-C6-10aryl, —C1-3alkylene-5-12 membered heteroaryl, C1-6alkyl,wherein the C1-3alkylene is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; wherein the aryl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, C1-3alkoxy, and C1-3aminoalkyl; wherein the C1-6alkyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, carboxyl, —CN, —OH, —NH2, C1-3alkyl, and C1-3alkoxy; * is the connecting end of R and A; L3 is selected from —C1-6alkylene-, —C2-6alkenylene-, —C2-6alkynylene-, —C1-3alkylene-C6-10aryl-C6-10aryl-C1-3alkylene-, —C1-3alkylene-C6-10aryl-5-12 membered heteroaryl-C1-3alkylene-, —C1-3alkylene-5-12 membered heteroaryl-C6-10aryl-C1-3alkylene-, —C1-3alkylene-5-12 membered heteroaryl-5-12 membered heteroaryl-C1-3alkylene-,the alkylene, alkenylene, and alkynylene are optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; wherein the aryl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, C1-3alkyl, and C1-3alkoxy; * is the connecting end of L3 and A;each of rings W1, W2, and W3 is independently selected from C6-12aryl, 5-12 membered heteroaryl, C6-14cycloalkyl, 5-12 membered heterocyclyl; wherein the aryl, heteroaryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more substituents independently selected from deuterium, halogen, —CN, C1-3alkyl, and C1-3alkoxy;each of Z11, Z12, Z21, Z22, Z31, and Z32 is independently selected from a bond, —C1-4alkylene-, —C1-4oxaalkylene-, —C1-4thiaalkylene-, —C1-4azaalkylene-; wherein the alkylene, oxaalkylene, thiaalkylene, and azaalkylene are optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, C1-3alkyl, and C1-3alkoxy;each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 is independently selected from H and deuterium;provided that when A is N, L1, L2, and L3 are not at the same timeprovided that when A is N, R isL1 and L2 arenot at the same time, * is the connecting end of R and A;the heteroatom in the heterocyclyl or heteroaryl is independently selected from O, N or S, and the number of heteroatoms is 1, 2, or 3.In an embodiment for the compound represented by the above formula (I-1-P2), R is a group containing L3; L1, L2 and L3 are groups containing Z11, Z21 and Z31 respectively, and one and only one of Z11, Z21 and Z31 is a group containing a double bond; the double bond is, for example, a double bond between C and O in —C(O)—, or a double bond between C and S in —C(S)—; further preferably, Z11, Z21 and Z31 are different from each other, or two groups not containing the double bond in Z11, Z21 and Z31 are the same and the two same groups contain —O—, —NH—, —S—, or —Se—, preferably, —O—; still further preferably, Z11, Z21 and Z31 each independently have a molecular weight of 14.0-107.1, preferably 14.0-60; preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60; still more preferably, Z11, Z21 and Z31 are selected from —CH2—, —CD2—, —CH2CH2—, —CD2CH2—, —C(O)—, —CH2C(O)—, —NHC(O)—, —OC(O)—, —CH2CH2O—, —OCH2C(O)—, —CH2OC(O)—, —CH2CH2CH2O—, and —S—C(O)—.In some embodiments, a compound represented by the following Formula (I-1-P3), or a pharmaceutically acceptable salt thereof is provided:wherein, is a single bond or a double bond;A is CRX, P, P(O), N, C6-12 aryl, 5-14 membered heteroaryl, and 5-18 membered heterocyclyl; wherein the aryl, heteroaryl, and heterocyclyl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, C1-3alkyl, and C1-3alkoxy;when is a single bond; RX is H, —OH, or C1-3alkoxy;when is a double bond, RX does not exist;L1 is selected from —C1-3alkylene-C6-10aryl-C6-10aryl-C1-3alkylene-, —C1-3alkylene-C6-10aryl-5-12 membered heteroaryl-C1-3alkylene-, —C1-3 alkylene-5-12 membered heteroaryl-5-12 membered heteroaryl-C1-3alkylene-, andwherein the C1-3alkylene is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; wherein the aryl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, and C1-3alkoxy; * is the connecting end of L1 and A;L2 is selected from —C1-3alkylene-C6-10aryl-C6-10aryl-C1-3alkylene-, —C1-3alkylene-C6-10aryl-5-12 membered heteroaryl-C1-3alkylene-, —C1-3alkylene-5-12 membered heteroaryl-5-12 membered heteroaryl-C1-3alkylene-, andwherein the C1-3alkylene is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; wherein the aryl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, and C1-3alkoxy; * is the connecting end of L2 and A;R is selected from H, —C1-3alkylene-C6-10aryl, —C1-3alkylene-5-12 membered heteroaryl, C1-6alkyl, andwherein the C1-3alkylene is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; wherein the aryl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, C1-3alkoxy, and C1-3aminoalkyl; wherein the C1-6alkyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, carboxyl, —CN, —OH, —NH2, C1-3alkyl, and C1-3alkoxy; * is the connecting end of R and A; L3 is selected from —C1-6alkylene-, —C2-6alkenylene-, —C2-6alkynylene-, —C1-3alkylene-C6-10aryl-C6-10aryl-C1-3alkylene-, —C1-3alkylene-C6-10aryl-5-12 membered heteroaryl-C1-3alkylene-, —C1-3alkylene-5-12 membered heteroaryl-C6-10aryl-C1-3alkylene-, —C1-3alkylene-5-12 membered heteroaryl-5-12 membered heteroaryl-C1-3alkylene-, andwherein the alkylene, alkenylene, and alkynylene are optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; wherein the aryl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, C1-3alkyl, and C1-3alkoxy; * is the connecting end of L3 and A;each of rings W1, W2, and W3 is independently selected from C6-12aryl, 5-12 membered heteroaryl, C6-14cycloalkyl, and 5-12 membered heterocyclyl; wherein the aryl, heteroaryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more substituents independently selected from deuterium, halogen, —CN, C1-3alkyl, and C1-3alkoxy;each of Z11, Z12, Z21, Z22, Z31, and Z32 is independently selected from a bond, —C1-4alkylene-, —C1-4oxaalkylene-, —C1-4thiaalkylene-, and —C1-4azaalkylene-; wherein the alkylene, oxaalkylene, thiaalkylene, and azaalkylene are optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, and C1-3haloalkoxy;each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 is independently selected from H and deuterium;provided that when A is N, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 are all H, L1, L2, and L3 are notat the same time;provided that when A is N, R isand R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 are all H, L1 and L2 are notat the same time, and * is the connecting end of R and A;provided that it is notthe heteroatom in the heterocyclyl or heteroaryl is independently selected from O, N, or S, and the number of heteroatoms is 1, 2, 3, or 4.In an embodiment for the compound represented by the above formula (I-1-P3), R is a group containing L3; L1, L2 and L3 are groups containing Z11, Z21 and Z31 respectively, and one and only one of Z11, Z21 and Z31 is a group containing a double bond; the double bond is, for example, a double bond between C and O in —C(O)—, or a double bond between C and S in —C(S)—; further preferably, Z11, Z21 and Z31 are different from each other, or two groups not containing the double bond in Z11, Z21 and Z31 are the same and the two same groups contain —O—, —NH—, —S—, or —Se—, preferably, —O—; still further preferably, Z11, Z21 and Z31 each independently have a molecular weight of 14.0-107.1, preferably 14.0-60; preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60; still more preferably, Z11, Z21 and Z31 are selected from —CH2—, —CD2—, —CH2CH2—, —CD2CH2—, —C(O)—, —CH2C(O)—, —NHC(O)—, —OC(O)—, —CH2CH2O—, —OCH2C(O)—, —CH2OC(O)—, —CH2CH2CH2O—, and —S—C(O)—.In some embodiments, a compound represented by the following Formula (I-1-P4), or a pharmaceutically acceptable salt thereof is provided:wherein, is a single bond or a double bond;A is CRX, P, P(O), N, C6-12aryl, 5-14membered heteroaryl, or 5-18membered heterocyclyl; the aryl, heteroaryl, and heterocyclyl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, C1-3alkyl, and C1-3alkoxy;when is a single bond, RX is H, —OH, or C1-3alkoxy;when is a double bond, RX does not exist;L1 is selected from —C1-3alkylene-C6-10aryl-C6-10aryl-C1-3alkylene-, —C1-3alkylene-C6-10aryl-5-12 membered heteroaryl-C1-3alkylene-, —C1-3alkylene-5-12 membered heteroaryl-5-12 membered heteroaryl-C1-3alkylene-, andthe C1-3alkylene is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; the aryl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, and C1-3alkoxy; * is the connecting end of L1 and A;L2 is selected from —C1-3alkylene-C6-10aryl-C6-10aryl-C1-3alkylene-, —C1-3alkylene-C6-10aryl-5-12 membered heteroaryl-C1-3alkylene-, —C1-3alkylene-5-12 membered heteroaryl-5-12 membered heteroaryl-C1-3alkylene-, andthe C1-3alkylene is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; the aryl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, and C1-3alkoxy; * is the connecting end of L2 and A;R is selected from H, —C1-3alkylene-C6-10aryl, —C1-3alkylene-5-12 membered heteroaryl, C1-6alkyl, andthe C1-3alkylene is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; the aryl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, C1-3alkoxy, and C1-3aminoalkyl; the C1-6alkyl isoptionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, carboxyl, —CN, —OH, —NH2, C1-3alkyl, and C1-3alkoxy; * is the connecting end of R and A;L3 is selected from —C1-6alkylene-, —C2-6alkenylene-, —C2-6alkynylene-, —C1-3alkylene-C6-10aryl-C6-10aryl-C1-3alkylene-, —C1-3alkylene-C6-10aryl-5-12 membered heteroaryl-C1-3alkylene-, —C1-3alkylene-5-12 membered heteroaryl-C6-10aryl-C1-3alkylene-, —C1-3alkylene-5-12 membered heteroaryl-5-12 membered heteroaryl-C1-3alkylene-, andthe alkylene, alkenylene, and alkynylene are optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; the aryl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, C1-3alkyl, and C1-3alkoxy; * is the connecting end of L3 and A;each of rings W1, W2, and W3 is independently selected from C6-12 aryl, 5-12 membered heteroaryl, C6-14cycloalkyl, and 5-12 membered heterocyclyl; the aryl, heteroaryl, cycloalkyl, and heterocyclyl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, —OH, —NH2, —CHO, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, C1-3haloalkoxy, —N(C1-3alkyl)2, —NH(C1-3alkyl), and —C(O)C1-3alkyl;each of Z11, Z12, Z21, Z22, Z31, and Z32 is independently selected from a bond, —O—, —S—, —NH—, —Se—, —C1-4alkylene-, —C1-8oxaalkylene-, —C1-4thiaalkylene-, —C1-4azaalkylene-, and —C1-4selenaalkylene-; the alkylene, oxaalkylene, thiaalkylene, azaalkylene, and selenaalkylene are optionally substituted by one or more substituents independently selected from Z41; Z41 is independently selected from deuterium, halogen, oxo, thio, —CN, —OH, —NH2, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, and C1-3haloalkoxy; or any two Z41 together with the atom to which they are attached form C3-6cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl;each of R31, R32, and R33 is independently selected from hydrogen, deuterium, halogen, C1-6alkyl, C1-6haloalkyl, C1-6deuteroalkyl, C1-6alkoxy, C1-6haloalkoxy, and C1-6deuteroalkoxy;each of h1, h2, h3, h4, h5, and h6 is independently 0, 1, or 2;each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 is independently selected from H, and deuterium;provided that when A is N, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 are all H, L1, L2, and L3 are notat the same time;provided that when A is N, R isand R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 are all H, L1 and L2 are notat the same time, * is the connecting end of R and A;provided that the compound is notthe heteroatom in the heterocyclyl and heteroaryl is independently selected from O, N and S, and the heteroatom number is 1, 2, 3, or 4;In an embodiment for the compound represented by the above formula (I-1-P4), R is a group containing L3; L1, L2 and L3 are groups containing Z11, Z21 and Z31 respectively, and one and only one of Z11, Z21 and Z31 is a group containing a double bond; the double bond is, for example, a double bond between C and O in —C(O)—, or a double bond between C and S in —C(S)—; further preferably, Z11, Z21 and Z31 are different from each other, or two groups not containing the double bond in Z11, Z21 and Z31 are the same and the two same groups contain —O—, —NH—, —S—, or —Se—, preferably, —O—; still further preferably, Z11, Z21 and Z31 each independently have a molecular weight of 14.0-107.1, preferably 14.0-60; preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60; still more preferably, Z11, Z21 and Z31 are selected from —CH2—, —CD2—, —CH2CH2—, —CD2CH2—, —C(O)—, —CH2C(O)—, —NHC(O)—, —OC(O)—, —CH2CH2O—, —OCH2C(O)—, —CH2OC(O)—, —CH2CH2CH2O—, and —S—C(O)—.In some embodiments, a compound represented by the following Formula (I-2), or a pharmaceutically acceptable salt thereof is provided:wherein, A, , L1, L2, R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R31, and R32 are defined as in the compound of Formula (I), Formula (I-1-P1), Formula (I-1-P2), Formula (I-1-P3), or Formula (I-1-P4).In an embodiment for the compound represented by the above formula (I-2), R is a group containing L3; L1, L2 and L3 are groups containing Z11, Z21 and Z31 respectively, and one and only one of Z11, Z21 and Z31 is a group containing a double bond; the double bond is, for example, a double bond between C and O in —C(O)—, or a double bond between C and S in —C(S)—; further preferably, Z11, Z21 and Z31 are different from each other, or two groups not containing the double bond in Z11, Z21 and Z31 are the same and the two same groups contain —O—, —NH—, —S—, or —Se—, preferably, —O—; still further preferably, Z11, Z21 and Z31 each independently have a molecular weight of 14.0-107.1, preferably 14.0-60; preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60; still more preferably, Z11, Z21 and Z31 are selected from —CH2—, —CD2—, —CH2CH2—, —CD2CH2—, —C(O)—, —CH2C(O)—, —NHC(O)—, —OC(O)—, —CH2CH2O—, —OCH2C(O)—, —CH2OC(O)—, —CH2CH2CH2O—, and —S—C(O)—.In some embodiments, a compound represented by the following Formula (I-3), or a pharmaceutically acceptable salt thereof is provided:In the formula, A, , L1, L2, R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 are defined as in the compound of Formula (I), Formula (I-1-P1), Formula (I-1-P2), Formula (I-1-P3), or Formula (I-1-P4).In one embodiment of the invention, A is CRX, P, P(O), N, phenyl, 5-6 membered heterocyclic group, or 12 membered heterocyclic group; wherein the heteroatom in the heterocyclic group is N, and the number of heteroatoms is 1, 2, 3 or 4.In an embodiment for the compound represented by the above formula (1-3), R is a group containing L3; L1, L2 and L3 are groups containing Z11, Z21 and Z31 respectively, and one and only one of Z11, Z21 and Z31 is a group containing a double bond; the double bond is, for example, a double bond between C and O in —C(O)—, or a double bond between C and S in —C(S)—; further preferably, Z11, Z21 and Z31 are different from each other, or two groups not containing the double bond in Z11, Z21 and Z31 are the same and the two same groups contain —O—, —NH—, —S—, or —Se—, preferably, —O—; still further preferably, Z11, Z21 and Z31 each independently have a molecular weight of 14.0-107.1, preferably 14.0-60; preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60; still more preferably, Z11, Z21 and Z31 are selected from —CH2—, —CD2—, —CH2CH2—, —CD2CH2—, —C(O)—, —CH2C(O)—, —NHC(O)—, —OC(O)—, —CH2CH2O—, —OCH2C(O)—, —CH2OC(O)—, —CH2CH2CH2O—, and —S—C(O)—.In one embodiment of the invention, A is CRX, P, P(O), N, phenyl, piperazinyl,orIn one embodiment of the invention, A is CRX, P, P(O), N,preferably A is N,In one embodiment of the invention, A is CRX, P, P(O), or N.In one embodiment of the invention, A is N.In one embodiment of the invention, A is P (O);In one embodiment of the invention, A is selected from CRX; RX is H, —OH, or methoxy.In one embodiment of the invention, A is selected from C—OH and C—OCH3.In one embodiment of the invention, A is a 6-12 membered heterocyclic group.In one embodiment of the invention, A is a 6 membered heterocyclic group; preferably, A is piperazinyl; preferablyIn one embodiment of the invention, A isIn one embodiment of the invention, A is phenyl; preferablyIn one embodiment of the invention, RX is H, —OH, or methoxy.In one embodiment of the invention, L1 is selected from -methylene-C6-10aryl-C6-10 aryl-methylene-, -methylene-5-12 membered heteroaryl-5-12 membered heteroaryl-methylene-, andwherein the methylene is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; wherein the aryl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, and C1-3alkoxy; * is the connecting end of L1 and A.In one embodiment of the invention, L1 is selected from —C1-3alkylene-phenyl-phenyl-C1-3alkylene-, —C1-3alkylene-5-6 membered heteroaryl-5-6 membered heteroaryl-C1-3alkylene-, andwherein the C1-3alkylene is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; wherein the phenyl and heteroaryl are optionally substituted by one or more substituents independently selected from halogen, —CN, and C1-3alkoxy; * is the connecting end of L1 and N.In one embodiment of the invention, L1 is selected from-methylene-phenyl-phenyl-methylene-,-ethylene-phenyl-phenyl-ethylene-, -methylene-5-6 membered heteroaryl-5-6 membered heteroaryl-methylene-, -ethylene-5-6 membered heteroaryl-5-6 membered heteroaryl-ethylene-, andwherein the methylene and ethylene are optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; wherein the phenyl and heteroaryl are optionally substituted by one or more substituents independently selected from halogen, —CN, and C1-3alkoxy; * is the connecting end of L1 and A. In one embodiment of the invention, L1 is selected from-methylene-phenyl-phenyl-methylene-, -methylene-6-membered heteroaryl-6-membered heteroaryl-methylene-, andwherein the methylene is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; wherein the phenyl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, and C1-3alkoxy; * is the connecting end of L1 and A.In one embodiment of the invention, L1 is selected from-methylene-phenyl-phenyl-methylene-, -methylene-pyridyl-pyridyl-methylene-, and* is the connecting end of L1 and A.In one embodiment of the invention, L1 is selected from* is the connecting end of L1 and A.In one embodiment of the invention, L1 is* is the connecting end of L1 and A.In one embodiment of the invention, L2 is selected from-methylene-C6-10aryl-C6-10aryl-methylene-, -methylene-5-12 membered heteroaryl-5-12 membered heteroaryl-methylene-, andwherein the methylene is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; wherein the aryl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, and C1-3alkoxy; * is the connecting end of L2 and A.In one embodiment of the invention, L2 is selected from —C1-3alkylene-phenyl-phenyl-C1-3alkylene-, —C1-3alkylene-5-6 membered heteroaryl-5-6 membered heteroaryl-C1-3alkylene-, andwherein the C1-3alkylene is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; wherein the phenyl and heteroaryl are optionally substituted by one or more substituents independently selected from halogen, —CN, and C1-3alkoxy; * is the connecting end of L2 and N.In one embodiment of the invention, L2 is selected from-methylene-phenyl-phenyl-methylene-, -ethylene-phenyl-phenyl-ethylene-, -methylene-5-6 membered heteroaryl-5-6 membered heteroaryl-methylene-, -ethylene-5-6 membered heteroaryl-5-6 membered heteroaryl-ethylene-, andwherein the methylene and ethylene are optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; wherein the phenyl and heteroaryl are optionally substituted by one or more substituents independently selected from halogen, —CN, and C1-3alkoxy; * is the connecting end of L2 and A. In one embodiment of the invention, L2 is selected from-methylene-phenyl-phenyl-methylene-, -methylene-6-membered heteroaryl-6-membered heteroaryl-methylene-, andwherein the methylene is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; wherein the phenyl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, and C1-3alkoxy; * is the connecting end of L2 and A.In one embodiment of the invention, L2 is selected from-methylene-phenyl-phenyl-methylene-, -methylene-pyridyl-pyridyl-methylene-, and* is the connecting end of L2 and A.In one embodiment of the invention, L2 is selected fromis the connecting end of L2 and A.In one embodiment of the invention, L2 is selected from* is the connecting end of L2 and A.In one embodiment of the invention, R is selected from H, —C1-3alkylene-C6-10aryl, —C1-3alkylene-5-12 membered heteroaryl, C1-6alkyl, andwherein the C1-3alkylene is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; wherein the aryl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, C1-3alkoxy, and C1-3aminoalkyl; wherein the C1-6alkyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, carboxyl, —CN, —OH, —NH2, C1-3alkyl, and C1-3alkoxy; * is the connecting end of R and A.In one embodiment of the invention, R is selected from H, —C1-3alkylene-C6-10aryl, —C1-3alkylene-5-membered heteroaryl, C1-6alkyl, andwherein the C1-3alkylene is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, and —NH2; wherein the aryl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, methoxy, and C1-3aminoalkyl; and wherein the C1-6alkyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, carboxyl, —CN, —OH, —NH2, C1-3alkyl, and C1-3alkoxy; * is the connecting end of R and A.In one embodiment of the invention, R is selected from H, -methylene-phenyl, -ethylene-phenyl, -methylene-5-6 membered heteroaryl, -ethylene-5-6 membered heteroaryl, C1-6alkyl, andwherein the methylene and ethylene are optionally substituted by one or more substituents independently selected from halogen, oxo, —CN, —OH, and —NH2; wherein the phenyl and heteroaryl are optionally substituted by one or more substituents independently selected from halogen, —CN, methoxy, andwherein the C1-6alkyl is optionally substituted by one or more substituents independently selected from halogen, oxo, carboxyl, —CN, —OH, and —NH2; * is the connecting end of R and A.In one embodiment of the invention, R is selected from H, -methylene-phenyl, -ethylene-phenyl, -methylene-pyridinyl, -ethylene-pyridinyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, andwherein the phenyl and pyridinyl are optionally substituted by one or more substituents independently selected from halogen, methoxy, andwherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, and n-hexyl are optionally substituted by one or more substituents independently selected from carboxyl and —NH2; * is the connecting end of R and A.In one embodiment of the invention, R is selected from H, —C1-3alkylene-phenyl, —C1-3alkylene-5-6 membered heteroaryl, and C1-6alkyl; wherein the C1-3alkylene is optionally substituted by one or more substituents independently selected from halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; wherein the phenyl and heteroaryl are optionally substituted by one or more substituents independently selected from halogen, —CN, C1-3alkoxy, and C1-3aminoalkyl; wherein the C1-6alkyl is optionally substituted by one or more substituents independently selected from halogen, carboxyl, —NH2, methyl, and methoxy.In one embodiment of the invention, R is selected from H,* is the connecting end of R and A.In one embodiment of the invention, R is selected from H,wherein, * is the connecting end with A.In one embodiment of the invention, L3 is selected from —C1-6alkylene-, —C2-6alkynylene-, -methylene-C6-10aryl-C6-10aryl-methylene-, -methylene-5-12 membered heteroaryl-5-12 membered heteroaryl-methylene-, andwherein the alkylene, methylene, and alkynylene are optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; wherein the aryl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, C1-3alkyl, and C1-3alkoxy; * is the connecting end of L3 and A.In one embodiment of the invention, L3 is selected from —C1-6alkylene-, —C2-6alkynylene-, -methylene-ethylene-phenyl-phenyl-ethylene-, -methylene-5-6 membered phenyl-phenyl-methylene-, heteroaryl-5-6 membered heteroaryl-methylene-, -ethylene-5-6 membered heteroaryl-5-6 membered heteroaryl-ethylene-, andwherein the alkylene, methylene, ethylene, and alkynylene are optionally substituted by one or more substituents independently selected from halogen, oxo, —CN, —OH, —NH2, methyl, and ethyl; wherein the phenyl and heteroaryl are optionally substituted by one or more substituents independently selected from halogen, —CN, methyl, ethyl, methoxy, and ethoxy; * is the connecting end of L3 and A.In one embodiment of the invention, L3 is selected from —C1-6alkylene-, —C2-6alkynylene-, -methylene-phenyl-phenyl-methylene-, -methylene-6-membered heteroaryl-6-membered heteroaryl-methylene-, andwherein the alkylene and methylene are optionally substituted by one or more substituents independently selected from F, Cl, Br, oxo, —CN, —OH, and —NH2; wherein the phenyl and heteroaryl are optionally substituted by one or more substituents independently selected from F, Cl, Br, —CN, methyl, ethyl, methoxy, and ethoxy; * is the connecting end of L3 and A.In one embodiment of the invention, L3 is selected from methylene, ethylene, n-propylidene, isopropylidene, n-butylene, n-pentylene, n-hexylene, n-propynylene, n-butynylene, n-pentynylene, n-hexynylidene, -methylene-phenyl-phenyl-methylene-, -methylene-pyridyl-pyridyl-methylene-, and* is the connecting end of L3 and A.In one embodiment of the invention, L3 is selected from* is the connecting end of L3 and A.In one embodiment of the invention, L3 is selected from* is the connecting end of L3 and A.In one embodiment of the invention, each of rings W1, W2, and W3 is independently selected from C6-12aryl, 5-12-membered heteroaryl, and C6-14cycloalkyl; wherein the aryl, heteroaryl, and cycloalkyl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, C1-3alkyl, and C1-3alkoxy.In one embodiment of the invention, each of rings W1, W2, and W3 is independently selected from C6-10aryl, 5-10-membered heteroaryl, and C6-10cycloalkyl; wherein the aryl, heteroaryl, and cycloalkyl are optionally substituted by one or more substituents independently selected from F, Cl, Br, —CN, methyl, ethyl, methoxy, and ethoxy.In one embodiment of the invention, each of rings W1, W2, and W3 is independently selected from phenyl, naphthyl, 8-10-membered bicyclic heteroaryl, C8-10bicyclic cycloalkyl, and 5-6-membered monocyclic heteroaryl; wherein the phenyl, naphthyl, heteroaryl, and cycloalkyl are optionally substituted by one or more substituents independently selected from halogen, —CN, C1-3alkyl, and C1-3alkoxy.In one embodiment of the invention, each of rings W1, W2, and W3 is independently selected from phenyl, naphthyl, 5-membered / 5-membered fused heteroaryl, 5-membered / 6-membered fused heteroaryl, 6-membered / 5-membered fused heteroaryl, 6-membered / 6-membered fused heteroaryl, 4-membered / 6-membered spirocycloalkyl, 6-membered / 4-membered spirocycloalkyl, 5-membered / 5-membered spirocycloalkyl, 5-membered / 6-membered spirocycloalkyl, 6-membered / 5-membered spirocycloalkyl, 6-membered / 6-membered spirocycloalkyl, and 5-6-membered monocyclic heteroaryl; wherein the phenyl, naphthyl, fused heteroaryl, spirocycloalkyl, and monocyclic heteroaryl are optionally substituted by one or more substituents independently selected from F, Cl, Br, —CN, methyl, ethyl, methoxy, and ethoxy.In one embodiment of the invention, each of rings W1, W2, and W3 is independently selected from phenyl, naphthyl, 5-membered / 5-membered fused heteroaryl, 5-membered / 6-membered fused heteroaryl, 6-membered / 5-membered fused heteroaryl, 6-membered / 6-membered fused heteroaryl, 4-membered / 6-membered spirocycloalkyl, 6-membered / 4-membered spirocycloalkyl, and 5-6-membered monocyclic heteroaryl; wherein the phenyl, naphthyl, fused heteroaryl, spirocycloalkyl, and monocyclic heteroaryl are optionally substituted by one or more substituents independently selected from F, Cl, Br, methyl, ethyl, methoxy, and ethoxy.In one embodiment of the invention, each of rings W1, W2, and W3 is independently selected from phenyl and 5-6 membered monocyclic heteroaryl; wherein the phenyl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, —OH, —NH2, —CHO, C1-3alkyl, C1-3alkoxy, —N(C1-3alkyl)2, —NH(C1-3alkyl), and —C(O)C1-3alkyl; wherein the heteroatom in the heteroaryl is O, N or S, and the number of heteroatoms is 1 or 2.In one embodiment of the invention, each of ring W1, W2, and W3 is independently selected from the following optionally substituted groups:wherein “optionally substituted” refers to unsubstituted or substituted by one or more substituents independently selected from deuterium, halogen, —CN, —OH, —NH2, —CHO, C1-3alkyl, C1-3alkoxy, —N(C1-3alkyl)2, —NH(C1-3alkyl), and —C(O)C1-3alkyl.In one embodiment of the invention, each of rings W1, W2, and W3 is independently selected from the following optionally substituted groups:wherein “optionally substituted” refers to unsubstituted or substituted by one or more substituents independently selected from deuterium, F, Cl, Br, —CN, —OH, —NH2, —CHO, methyl, ethyl, methoxy, ethoxy, —N(CH3)2, —NH(CH3), and —C(O) CH3.In one embodiment of the invention, each of rings W1, W2, and W3 is independently selected from phenyl and thienyl; wherein the phenyl and thienyl are optionally substituted by one or more substituents independently selected from deuterium, F, Cl, Br, —CN, —OH, —NH2, —CHO, methyl, ethyl, methoxy, ethoxy, —N(CH3)2, —NH(CH3), and —C(O) CH3.In one embodiment of the invention, each of rings W1, W2, and W3 is independently selected from the following optionally substituted groups:wherein “optionally substituted” refers to unsubstituted or substituted by one or more substituents independently selected from deuterium, F, Cl, Br, —CN, —OH, —NH2, —CHO, methyl, ethyl, methoxy, ethoxy, —N(CH3)2, —NH(CH3), and —C(O) CH3.In one embodiment of the invention, each of rings W1, W2, and W3 is independently selected from phenyl; wherein the phenyl is optionally substituted by one or more substituents independently selected from F, Cl, Br, methyl, ethyl, methoxy, and ethoxy.In one embodiment of the invention, each of W1, W2, and W3 is independently selected fromIn one embodiment of the invention, each of Z11, Z12, Z21, Z22, Z31, and Z32 is independently selected from a bond, —O—, —S—, —NH—, —Se—, —C1-4alkylene-, —C1-6oxaalkylene-, —C1-4thiaalkylene-, —C1-4azaalkylene-, and —C1-4selenaalkylene-; wherein the alkylene, oxaalkylene, thiaalkylene, azaalkylene, and selenaalkylene are optionally substituted by one or more substituents selected from Z41; Z41 is independently selected from deuterium, halogen (e.g., F, Cl), oxo, thio, —CN, —OH, —NH2, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, and C1-3haloalkoxy; or any two Z41 together with the atom to which they are attached form C3-6cycloalkyl, and 3-6 membered heterocyclyl (e.g., oxetanyl); wherein the heteroatom in the heterocyclyl is O, N or S, and the number of heteroatoms is 1 or 2.In one embodiment of the invention, each of Z11, Z12, Z21, Z22, Z31, and Z32 is independently selected from a bond, —C1-3alkylene-, —C1-3oxaalkylene-, —C1-3thiaalkylene-, and —C1-3azaalkylene-; wherein the alkylene, oxaalkylene, thiaalkylene, and azaalkylene are optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, methyl, and methoxy; preferably, wherein the alkylene, oxaalkylene, thiaalkylene, and azaalkylene are optionally substituted by one or more substituents independently selected from deuterium and oxo.In one embodiment of the invention, each of Z11, Z12, Z21, Z22, Z31, and Z32 is independently selected from —C1-2alkylene-, —C1-2oxaalkylene-, —C1-2thiaalkylene-, and —C1-2azaalkylene-; wherein the alkylene, oxaalkylene, thiaalkylene, and azaalkylene are optionally substituted by one or more substituents independently selected from deuterium and oxo.In one embodiment of the invention, each of Z11, Z12, Z21, Z22, Z31, and Z32 is independently selected from a bond, —C1-3alkylene-, and —C1-3oxaalkylene-; wherein the alkylene and oxaalkylene are optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, methyl, and methoxy; preferably, the alkylene and oxaalkylene are optionally substituted by one or more substituents independently selected from deuterium and oxo.In one embodiment of the invention, each of Z11, Z12, Z21, Z22, Z31, and Z32 is independently selected from —C1-2alkylene-, —C1-3oxaalkylene-, and —C1-3azaalkylene-; wherein the alkylene, oxaalkylene, and azaalkylene are optionally substituted by one or more substituents independently selected from oxo.In one embodiment of the invention, when Z11, Z21, and Z31 are present in the compound at the same time, in a combination of the definitions of Z11, Z21, and Z31, at least one heteroatom or heteroatom group is present, and the heteroatom or heteroatom group is selected from —O—, —S—, —Se—, —NH—, —CO—, and —C(S)—;In one embodiment of the invention, when Z11, Z21, and Z31 are present in the compound at the same time, in a combination of the definitions of Z11, Z21, and Z31, at least one heteroatom or heteroatom group is present, and the heteroatom or heteroatom group is selected from —CO— or —C(S)—.In one embodiment of the invention, when Z11, Z21, and Z31 are present in the compound at the same time, in a combination of the definitions of Z11, Z21, and Z31, at least one group selected frompreferablyis present; * represents the connecting end with A.In one embodiment of the invention, when Z11, Z21, and Z31 are present in the compound at the same time, in a combination of the definitions of Z11, Z21, and Z31, at least one heteroatom or heteroatom group is present, and the heteroatom or heteroatom group is selected from —O—, —NH—, and —CO—.In one embodiment of the invention, when Z11, Z21, and Z31 are present in the compound at the same time, in a combination of the definitions of Z11, Z21, and Z31, 1-4 heteroatoms or heteroatom groups are present, the heteroatom or heteroatom group is selected from —O—, —S—, —Se—, —NH—, —CO—, and —C(S)—, and the number of heteroatoms or heteroatom groups is specifically 1, 2, 3, or 4; preferably 1-3 heteroatoms or heteroatom groups are present, and the number thereof is specifically 1, 2, or 3; or preferably 2-4 heteroatoms or heteroatom groups are present, and the number thereof is 2, 3, or 4; further preferably 2 or 3 heteroatoms or heteroatom groups are present; the heteroatom or heteroatom group is preferably —O—, —S—, —NH—, or —CO—; the heteroatom or heteroatom group is more preferably-O—, or —CO—; preferably, the heteroatom or heteroatom group at least comprises —CO— or —C(S)—.In one embodiment of the invention, Z21 contains a heteroatom or heteroatom group selected from-O—, —S—, —Se—, and —NH—; and Z31 contains a heteroatom or heteroatom group selected from —CO— and —C(S)—; and the total number of the heteroatoms or heteroatom groups in the combination of Z21 and Z31 is 1-4;In one embodiment of the invention, when Z11, Z21, and Z31 are present in the compound at the same time, in a combination of the definitions of Z11, Z21, and Z31, 1-4, preferably 1-3 and more preferably 2-3 heteroatoms or heteroatom groups are present, and the heteroatom or heteroatom group is selected from —O—, —NH—, and —CO—; preferably, the heteroatom or heteroatom group at least comprises —CO—.In one embodiment of the invention, Z11, Z21 and Z31 together contain 1-4 heteroatoms or heteroatom groups, wherein the heteroatoms or heteroatom groups are selected from —O—, —NH—, —CO—, and the number of heteroatoms or heteroatom groups is 1, 2, 3, and 4.In one embodiment of the invention, Z11, Z21 and Z31 together contain 1-3 heteroatoms or heteroatom groups, wherein the heteroatoms or heteroatom groups are selected from —O—, —NH—, and —CO—, specifically 1, 2, and 3.In one embodiment of the invention, Z11, Z21 and Z31 together contain 2-3 heteroatoms or heteroatom groups, wherein the heteroatoms or heteroatom groups are selected from —O—, —NH—, and —CO—, and the number of heteroatoms or heteroatom groups is 2 and 3; preferably, the heteroatoms or heteroatom groups contain at least —CO—.In one embodiment of the invention, each of Z11, Z12, Z21, Z22, Z31, and Z32 is independently selected from —CD2—, —C1-4alkylene-, —OC1-3alkylene-, —C(O)—, —C1-3alkylene-C(O)—, —OC1-3alkylene-C(O)—, —NH—C1-3alkylene-C(O)—, —S—C1-3alkylene-C(O)—, —O—C1-2alkylene-C(O)—C1-3alkylene-, —C1-2alkylene-O—C1-3alkylene-, —NH—C1-3alkylene-, —S—C1-3alkylene-, —C1-3alkylene-NH—C(O)—, —C1-3alkylene-O—C(O)—, —NH—C(O)—, —O—C(O)—, —S—C(O)—, —C1-3alkylene-C(S)—, —Se—C1-3alkylene-,wherein the alkylene, methylene, and ethylene are optionally substituted by one or more substituents independently selected from deuterium, F, and C1.In one embodiment of the invention, each of Z11, Z12, Z21, Z22, Z31, and Z32 is independently selected from —CD2—, —C1-3alkylene-, —OC1-3alkylene-, —C(O)—, —C1-3alkylene-C(O)—, —OC1-3alkylene-C(O)—, —NH—C1-3alkylene-C(O)—, —S—C1-3alkylene-C(O)—, —O—C1-3alkylene-C(O)—C1-3alkylene-, —C1-3alkylene-O—C1-3alkylene-, —NH—C1-3alkylene-, —S—C1-3alkylene-, —C1-3alkylene-NH—C(O)—, —C1-3alkylene-O—C(O)—, —NH—C(O)—, —O—C(O)—, and —S—C(O)—.In one embodiment of the invention, each of Z11, Z12, Z21, Z22, Z31, and Z32 is independently selected from a bond, —CD2—, —C1-3alkylene-, —OC1-3alkylene-, —C(O)—, —C1-3alkylene-C(O)—, —OC1-3alkylene-C(O)—, —NH—C1-3alkylene-C(O)—, —S—C1-3alkylene-C(O)—, and —O—C1-3alkylene-C(O)—C1-3alkylene-.In a preferred embodiment of the invention, each of Z11, Z12, Z21, Z22, Z31, and Z32 is independently selected from —C1-3alkylene-, —OC1-3alkylene-, —C1-3alkylene-C(O)—, —OC1-3alkylene-C(O)—, —NH—C(O)—, and —O—C(O)—.In one embodiment of the invention, each of Z11, Z12, Z21, Z22, Z31, and Z32 is independently selected from —CD2—, —C1-2alkylene-, —OC1-3alkylene-, —C(O)—, —C1-2alkylene-C(O)—, —OC1-2alkylene-C(O)—, —NH—C1-2alkylene-C(O)—, —S—C1-2alkylene-C(O)—, —O—C1-2alkylene-C(O)—C1-2alkylene-, —C1-2alkylene-O—C1-2alkylene-, —NH—C1-2alkylene-, —S—C1-2alkylene-, —C1-2alkylene-NH—C(O)—, —C1-2alkylene-O—C(O)—, —NH—C(O)—, —O—C(O)—, and —S—C(O)—.In one embodiment of the invention, each of Z11, Z12, Z21, Z22, Z31, and Z32 is independently selected from a bond, —CD2—, —C1-2alkylene-, —OC1-2alkylene-, —C(O)—, —C1-2alkylene-C(O)—, —OC1-2alkylene-C(O)—, —NH—C1-2alkylene-C(O)—, —S—C1-2alkylene-C(O)—, and —O—C1-2alkylene-C(O)—C1-2alkylene-.In one embodiment of the invention, each of Z11, Z12, Z21, Z22, Z31, and Z32 is independently selected from a bond, methylene, ethylene, —CD2—, —O—, —S—, —NH—,In one embodiment of the invention, each of Z11, Z12, Z21, Z22, Z31, and Z32 is independently selected from methylene, ethylene,In one embodiment of the invention, each of Z11, Z12, Z21, Z22, Z31, and Z32 is independently selected from methylene, ethylene,* represents the connecting end with A.In one embodiment of the invention, each of Z11, Z12, Z21, Z22, Z31, and Z32 is independently selected from methylene, ethylene, —CD2—,* represents the connecting end with A.In one embodiment of the invention, each of Z12, Z22 and Z32 is independently selected from methylene, and —CD2, and Z11 is selected from methylene, ethylene, —CD2—,and Z21 is selected from methylene, ethylene, —CD2—,and Z31 is selected fromfurther preferably Z31 is selected from* represents the connecting end with A.In one embodiment of the invention, each of Z12, Z22 and Z32 is independently selected from methylene, —CD2, and Z11 is selected from methylene, ethylene, —CD2—, and and Z21 isand Z31 is selected selected from methylene, ethylene, —CD2—,and Z31 is selected from* represents the connecting end with A.In one embodiment of the invention, each of Z11, Z12, Z21, Z22, Z31, and Z32 is independently selected from methylene, ethylene,In one embodiment of the invention, each of Z11, Z12, Z21, and Z22 is independently selected from CD2— and methylene, preferably methylene.In one embodiment of the invention, each of Z12, Z22, and Z32 is independently selected from —CD2—, methylene and ethylene.In one embodiment of the invention, Z12, Z22, and Z32 are all-CD2-or methylene, preferably methylene.In one embodiment of the invention, Z11 is selected from —CD2—, —C1-3alkylene- and —OC1-3alkylene-, and preferably —C1-3alkylene-; preferably, it is selected from —CD2—, methylene, ethylene, methyleneoxy, and ethyleneoxy, and more preferably methylene.In one embodiment of the invention, Z21 is selected from —OC1-3alkylene-, —NH—C1-3alkylene-, —S—C1-3alkylene-, —Se—C1-3alkylene-, and —C1-2alkylene-O—C1-3alkylene-; preferably —OC1-3alkylene-, —NH—C1-2alkylene-, —S—C1-2alkylene-, and —C1-2alkylene-O—C1-3alkylene-.In one embodiment of the invention, Z31 is selected from —C(O)—, —C1-3alkylene-C(O)—, —OC1-3alkylene-C(O)—, —NH—C1-3alkylene-C(O)—, —S—C1-3alkylene-C(O)—, —O—C1-2alkylene-C(O)—C1-3alkylene-, —C1-3alkylene-NH—C(O)—, —C1-3alkylene-O—C(O)—, —NH—C(O)—, —O—C(O)—, —S—C(O)—, and —C1-3alkylene-C(S)—; it is preferably selected from —C(O)—, —C1-2alkylene-C(O)—, —OC1-2alkylene-C(O)—, —NH—C(O)—, —O—C(O)—, and —S—C(O)—, preferably —C1-2alkylene-C(O)—, —OC1-2alkylene-C(O)—, —NH—C(O)—, —O—C(O)—, and —S—C(O)—; and preferably O-CH2C(O)—.In one embodiment of the invention, Z11 is independently selected from —OC1-3alkyl-, —NH—C1-3alkyl-, —S—C1-3alkyl-, —Se—C1-3alkyl-, and —C1-3alkyl-O—C1-3alkyl-; and Z21 is independently selected from-OC1-3alkyl-, —NH—C1-3alkyl-, —S—C1-3alkyl-, —Se—C1-3alkyl-, and —C1-3alkyl-O—C1-3alkyl-.In one embodiment of the invention, Z21 is selected from —OC1-3alkylene-, —NH—C1-3alkylene-, —S—C1-3alkylene-, —Se—C1-3alkylene-, and —C1-2alkylene-O—C1-3alkylene-; and Z31 is selected from —C(O)—, —C1-3alkylene-C(O)—, —OC1-3alkylene-C(O)—, —NH—C1-3alkylene-C(O)—, —S—C1-3alkylene-C(O)—, —O—C1-2alkylene-C(O)—C1-3alkyl-, —C1-3alkylene-NH—C(O)—, —C1-3alkylene-O—C(O)—, —NH—C(O)—, —O—C(O)—, —S—C(O)—, and —C1-3alkylene-C(S)—.In one embodiment of the invention, Z11 is selected from —CD2, —C1-3alkylene-, and OC1-3alkylene-; and Z21 is selected from —OC1-3alkylene-, —NH—C1-3alkylene-, —S—C1-3alkylene-, —Se—C1-3alkylene-, and —C1-2alkylene-O—C1-3alkylene-; and Z31 is selected from —C(O)—, —C1-3alkylene-C(O)—, —OC1-3alkylene-C(O)—, —NH—C1-3alkylene-C(O)—, —S—C1-3alkylene-C(O)—, —O—C1-2alkylene-C(O)—C1-3alkylene-, —C1-3alkylene-NH—C(O)—, —C1-3alkylene-O—C(O)—, —NH—C(O)—, —O—C(O)—, —S—C(O)—, and —C1-3alkylene-C(S)—.In one embodiment of the invention, Z11 is selected from —CD2—, —C1-3alkylene- and —OC1-3alkylene-; and Z21 is selected from —OC1-3alkylene-, —NH—C1-3alkylene-, —S—C1-3alkylene-, —Se—C1-3alkylene-, and —C1-2alkylene-O—C1-3alkylene-; and Z31 is selected from —C(O)—, —C1-3alkylene-C(O)—, —OC1-3alkylene-C(O)—, —NH—C1-3alkylene-C(O)—, —S—C1-3alkylene-C(O)—, —O—C1-2alkylene-C(O)—C1-3alkylene-, —C1-3alkylene-NH—C(O)—, —C1-3alkylene-O—C(O)—, —NH—C(O)—, —O—C(O)—, —S—C(O)—, and —C1-3alkylene-C(S)—.In one embodiment of the invention, Z11 is selected from —C1-3alkylene- and —OC1-3alkylene-; and Z21 is selected from —OC1-3alkylene-, —NH—C1-3alkylene-, —S—C1-3alkylene-, —Se—C1-3alkylene-, and —C1-2alkylene-O—C1-3alkylene-; and Z31 is selected from —C(O)—, —C1-3alkylene-C(O)—, —OC1-3alkylene-C(O)—, —NH—C1-3alkylene-C(O)—, —S—C1-3alkylene-C(O)—, —O—C1-2alkylene-C(O)—C1-3alkylene-, —C1-3alkylene-NH—C(O)—, —C1-3alkylene-O—C(O)—, —NH—C(O)—, —O—C(O)—, —S—C(O)—, and —C1-3alkylene-C(S)—.In one embodiment of the invention, Z11 is selected from —CD2, —C1-3alkylene-, and OC1-3alkylene-*; and Z21 is selected from —OC1-3alkylene-*, —NH—C1-3alkylene-*, —S—C1-3alkylene-*, —Se—C1-3alkylene-*, and —C1-2alkylene-O—C1-3alkylene-*; and Z31 is selected from —C(O)—, —C1-3alkylene-C(O)—*, —OC1-3alkylene-C(O)—*, —NH—C1-3alkylene-C(O)—*, —S—C1-3alkylene-C(O)—*, —O—C1-2alkylene-C(O)—C1-3alkylene-*, —C1-3alkylene-NH—C(O)—*, —C1-3alkylene-O—C(O)—*, —NH—C(O)—*, —O—C(O)—*, —S—C(O)—*, and —C1-3alkylene-C(S)—*; * represents the connecting end with A.In one embodiment of the invention, Z11 is selected from —CD2—, —C1-3 alkylene- and —OC1-3alkylene-*; and Z21 is selected from —OC1-3alkylene-*, —NH—C1-3alkylene-*, —S—C1-3alkylene-*, —Se—C1-3alkylene-*, and —C1-2alkylene-O—C1-3alkylene-*; and Z31 is selected from —C(O)—, —C1-3alkylene-C(O)—*, —OC1-3alkylene-C(O)—*, —NH—C1-3alkylene-C(O)—*, —S—C1-3alkylene-C(O)—*, —O—C1-2alkylene-C(O)—C1-3alkylene-*, —C1-3alkylene-NH—C(O)—*, —C1-3alkylene-O—C(O)—*, —NH—C(O)—*, —O—C(O)—*, —S—C(O)—*, and —C1-3alkylene-C(S)—*; * represents the connecting end with A.In one embodiment of the invention, Z11 is selected from —C1-3 alkylene- and —OC1-3alkylene-*; and Z21 is selected from —OC1-3alkylene-*, —NH—C1-3alkylene-*, —S—C1-3alkylene-*, —Se—C1-3alkylene-*, and —C1-2alkylene-O—C1-3alkylene-*; and Z31 is selected from —C(O)—, —C1-3alkylene-C(O)—*, —OC1-3alkylene-C(O)—*, —NH—C1-3alkylene-C(O)—*, —S—C1-3alkylene-C(O)—*, —O—C1-2alkylene-C(O)—C1-3alkylene-*, —C1-3alkylene-NH—C(O)—*, —C1-3alkylene-O—C(O)—*, —NH—C(O)—*, —O—C(O)—*, —S—C(O)—*, and —C1-3alkylene-C(S)—*; * represents the connecting end with A.In one embodiment of the invention, Z11 is selected from —CD2—, —C1-2alkylene-, and OC1-2alkylene-*; and Z21 is selected from —OC1-2alkylene-*, —NH—C1-2alkylene-*, —S—C1-2alkylene-*, —Se—C1-2alkylene-*, and —CH2—O—C1-2alkylene-*; and Z31 is selected from —C(O)—, —C1-2alkylene-C(O)—*, —OC1-2alkylene-C(O)—*, —NH—C1-2alkylene-C(O)—*, —S—C1-2alkylene-C(O)—*, —C1-2alkylene-NH—C(O)—*, —C1-2alkylene-O—C(O)—*, —NH—C(O)—*, —O—C(O)—*, —S—C(O)—*, and —C1-2alkylene-C(S)—*; further preferably, Z31 is selected from —C1-2alkylene-C(O)—*, —OC1-2alkylene-C(O)—*, —NH—C1-2alkylene-C(O)—*, —S—C1-2alkylene-C(O)—*, —C1-2alkylene-NH—C(O)—*, —C1-2alkylene-O—C(O)—*, —CH2NH—C(O)—*, —NH—C(O)—*, —O—C(O)—*, —S—C(O)—*, and —C1-2alkylene-C(S)—*; further preferably, Z31 is selected from —C1-2alkylene-C(O)—*, —OCH2—C(O)—*, —CH2—O—C(O)—*, —NH—C(O)—*, —O—C(O)—*, and —S—C(O)—*; further preferably, Z31 is selected from —CH2C(O)—*; * represents the connecting end with A.In one embodiment of the invention, each of L1 and L2 is independently selected from* represents the connecting end with A.In one embodiment of the invention, each of L1 and L2 is independently selected fromrepresents the connecting end with N (i.e. A).In one embodiment of the invention, L3 is selected from* represents the connecting end with A.In one embodiment of the invention, each of L1, L2, and L3 is independently selected from* represents the connecting end with N (i.e. A).In one embodiment of the invention, R is selected from H,* represents the connecting end with A.In one embodiment of the invention, R is selected from H,* represents the connecting end with A.Firstly, the invention provides a compound represented by the following Formula (I′-1), Formula (I′-2), or Formula (I′-3) or a pharmaceutically acceptable salt thereof:wherein A, L1, L2, R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R31, R32, R41, R42, R50, R51, h1, h2, h3, and h4 are defined as in the compound of Formula (I), Formula (I-1-P1), Formula (I-1-P2), Formula (I-1-P3), or Formula (I-1-P4).In an embodiment for the compound represented by the above Formula (I′-1), (I′-2), or (I′-3), R is a group containing L3; and one and only one of Z11, Z21 and Z31 is a group containing a double bond; the double bond is, for example, a double bond between C and O in —C(O)—, or a double bond between C and S in —C(S)—; further preferably, Z11, Z21 and Z31 are different from each other, or two groups not containing the double bond in Z11, Z21 and Z31 are the same and the two same groups contain —O—, —NH—, —S—, or —Se—, preferably, —O—; still further preferably, Z11, Z21 and Z31 each independently have a molecular weight of 14.0-107.1, preferably 14.0-60; preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60; still more preferably, Z11, Z21 and Z31 are selected from —CH2—, —CD2—, —CH2CH2—, —CD2CH2—, —C(O)—, —CH2C(O)—, —NHC(O)—, —OC(O)—, —CH2CH2O—, —OCH2C(O)—, —CH2OC(O)—, —CH2CH2CH2O—, and —S—C(O)—. The invention also provides a compound represented by the following Formula (II), or a pharmaceutically acceptable salt thereof:wherein, L1 and L2 are defined as in the compound of Formula (I), Formula (I-1-P1), Formula (I-1-P2), Formula (I-1-P3), or Formula (I-1-P4);R′ is selected from H, —C1-3alkylene-C6-10aryl, —C1-3alkylene-5-12 membered heteroaryl, and C1-6alkyl; wherein the C1-3alkylene is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; wherein the aryl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, C1-3alkoxy, and C1-3aminoalkyl; wherein the C1-6alkyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, carboxyl, —CN, —OH, —NH2, C1-3alkyl, and C1-3alkoxy.In one embodiment of the invention, R′ is selected from H, —C1-3alkylene-C6-10aryl, —C1-3alkylene-5-membered heteroaryl, and C1-6alkyl; wherein the C1-3alkylene is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, and —NH2; wherein the aryl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, methoxy, and C1-3aminoalkyl; and wherein the C1-6alkyl is optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, carboxyl, —CN, —OH, —NH2, C1-3alkyl, and C1-3alkoxy;L1 is* represents the connecting end with N;L2 is* represents the connecting end with N;each of rings W1 and W2 is independently selected from C6-12aryl and 5-12-membered heteroaryl;wherein the aryl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, C1-3alkyl, and C1-3alkoxy;each of Z11, Z12, Z21, and Z22 is independently selected from —C1-3alkylene-and —C1-3oxaalkylene-;wherein the alkylene and oxaalkylene are optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, methyl, and methoxy.In one embodiment of the invention, R′ is selected from H, —C1-3alkylene-phenyl, -methylene-5-6 membered heteroaryl, and C1-6alkyl; wherein the methylene and C1-3alkylene are optionally substituted by one or more substituents independently selected from halogen, oxo, —CN, —OH, —NH2, and C1-3alkyl; wherein the phenyl and heteroaryl are optionally substituted by one or more substituents independently selected from halogen, —CN, C1-3alkoxy, and C1-3aminoalkyl; wherein the C1-6alkyl is optionally substituted by one or more substituents independently selected from halogen, oxo, carboxyl, —CN, —OH, —NH2, C1-3alkyl, and C1-3alkoxy.In one embodiment of the invention, R′ is selected from H, -methylene-phenyl, -ethylene-phenyl, -methylene-pyridinyl, C1-6alkyl; wherein the phenyl and pyridinyl are optionally substituted by one or wherein the C1-more substituents independently selected from halogen, —CN, methoxy, andwherein the C1-6alkyl is optionally substituted by one or more substituents independently selected from carboxyl and —NH2.In one embodiment of the invention, R′ is selected from H,In one embodiment of the invention, each of rings W1 and W2 is independently selected from phenyl and 5-12-membered heteroaryl; wherein the phenyl and heteroaryl are optionally substituted by one or more substituents independently selected from halogen and CN.In one embodiment of the invention, each of rings W1 and W2 is independently selected from phenyl and 8-10-membered bicyclic heteroaryl; wherein the phenyl and bicyclic heteroaryl are optionally substituted by one or more substituents independently selected from halogen and —CN; wherein the heteroatoms in the bicyclic heteroaryl are independently selected from O, N or S, and the number of heteroatoms is 1 or 2.In one embodiment of the invention, each of rings W1 and W2 is independently selected fromIn one embodiment of the invention, each of Z11, Z12, Z21, and Z22 is independently selected from —C1-3alkylene-and —C1-3oxaalkylene-; wherein the alkylene and oxaalkylene are optionally substituted by one or more substituents independently selected from deuterium and oxo.In one embodiment of the invention, each of Z11, Z12, Z21, and Z22 is independently selected from methylene, ethylene,In one embodiment of the invention, each of L1 and L2 is independently selected fromrepresents the connecting end with N.The invention also provides a compound represented by the following Formula (II-A), (II-B), (II-C), (II-A′), (II-B′), or (II-C′), or a pharmaceutically acceptable salt thereof:wherein, W1, W2, and R′ are defined as in the compound of Formula (I), Formula (I-1-P1), Formula (I-1-P2), Formula (I-1-P3), Formula (I-1-P4) or Formula (II).The invention also provides a compound represented by the following Formula (III), or a pharmaceutically acceptable salt thereof:wherein, A, L1, L2, and L3 are defined as in the compound of Formula (I), Formula (I-1-P1), Formula (I-1-P2), Formula (I-1-P3), or Formula (I-1-P4).In an embodiment for the compound represented by the above formula (III), L1, L2 and L3 are groups containing Z11, Z21 and Z31 respectively, and one and only one of Z11, Z21 and Z31 is a group containing a double bond; the double bond is, for example, a double bond between C and O in —C(O)—, or a double bond between C and S in —C(S)—; further preferably, Z11, Z21 and Z31 are different from each other, or two groups not containing the double bond in Z11, Z21 and Z31 are the same and the two same groups contain —O—, —NH—, —S—, or —Se—, preferably, —O—; still further preferably, Z11, Z21 and Z31 each independently have a molecular weight of 14.0-107.1, preferably 14.0-60; preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60; still more preferably, Z11, Z21 and Z31 are selected from —CH2—, —CD2—, —CH2CH2—, —CD2CH2—, —C(O)—, —CH2C(O)—, —NHC(O)—, —OC(O)—, —CH2CH2O—, —OCH2C(O)—, —CH2OC(O)—, —CH2CH2CH2O—, and —S—C(O)—.The invention also provides a compound represented by the following Formula (III-1), or a pharmaceutically acceptable salt thereof:wherein, W1, W2, W3, Z11, Z12, Z21, Z22, Z31, and Z32 are defined as in the compound of Formula (I), Formula (I-1-P1), Formula (I-1-P2), Formula (I-1-P3), Formula (I-1-P4) or Formula (III).In one embodiment of the invention, each of Z12, Z22, and Z32 are independently selected from methylene and ethylene;each of Z11, Z21, and Z31 is independently selected from a bond, —C1-4alkylene-, —C1-6oxaalkylene-(e.g., —C1-4oxaalkylene-), —C1-4thiaalkylene-, —C1-4azaalkylene-, and —C1-4selenaalkylene-; wherein the alkylene, oxaalkylene, thiaalkylene, azaalkylene, and selenaalkylene are optionally substituted by one or more substituents selected from Z41; Z41 is independently selected from deuterium, halogen (e.g., F and Cl), oxo, thio, —CN, —OH, —NH2, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, and C1-3haloalkoxy; or any two Z41 together with the atoms to which they are attached form C3-6cycloalkyl or 3-6-membered heterocyclyl (e.g., oxetanyl); wherein the heteroatom in the heterocyclyl is O, N, or S, and the number of the heteroatom is 1;each of rings W1, W2, and W3 is independently selected from phenyl and 5-6 membered monocyclic heteroaryl; wherein the phenyl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, —OH, —NH2, —CHO, C1-3alkyl, C1-3alkoxy, —N(C1-3alkyl)2, —NH(C1-3alkyl), and —C(O)C1-3alkyl; wherein the heteroatom in the heteroaryl is O, N, or S, and the number of heteroatoms is 1 or 2.In one embodiment of the invention, Z12, Z22, and Z32 are all methylene.In one embodiment of the invention, when Z11, Z21, and Z31 are present in the compound at the same time, in a combination of the definitions of Z11, Z21, and Z31 2 or 3 heteroatoms or heteroatom groups are present, and the heteroatom or heteroatom group is selected from —O—, —S—, —NH—, and —CO—. In one embodiment of the invention, each of rings W1, W2, and W3 is independently selected from phenyl and thienyl; the phenyl and thienyl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, —OH, —NH2, —CHO, C1-3alkyl, C1-3alkoxy, —N(C1-3alkyl)2, —NH(C1-3alkyl), and —C(O)C1-3alkyl.In one embodiment of the invention, each of rings W1, W2, and W3 is independently selected fromthe above groups are optionally substituted by one or more substituents independently selected from deuterium, F, Cl, Br, methyl, ethyl, methoxy, and ethoxy.In an embodiment for the compound represented by the above formula (III-1), one and only one of Z11, Z21 and Z31 is a group containing a double bond; the double bond is, for example, a double bond between C and O in —C(O)—, or a double bond between C and S in —C(S)—; further preferably, Z11, Z21 and Z31 are different from each other, or two groups not containing the double bond in Z11, Z21 and Z31 are the same and the two same groups contain —O—, —NH—, —S—, or —Se—, preferably, —O—; still further preferably, Z11, Z21 and Z31 each independently have a molecular weight of 14.0-107.1, preferably 14.0-60; preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60; still more preferably, Z11, Z21 and Z31 are selected from —CH2—, —CD2—, —CH2CH2—, —CD2CH2—, —C(O)—, —CH2C(O)—, —NHC(O)—, —OC(O)—, —CH2CH2O—, —OCH2C(O)—, —CH2OC(O)—, —CH2CH2CH2O—, and —S—C(O)—.The invention also provides a compound represented by the following Formula (III-2), or a pharmaceutically acceptable salt thereof:wherein, W1, W2, W3, Z11, Z12, Z21, Z22, Z31, Z32, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R44, R45, R46, R47, R48, R49, R31, R32, and R33 are defined as in the compound of Formula (I), Formula (I-1-P1), Formula (I-1-P2), Formula (I-1-P3), Formula (I-1-P4), Formula (III) or Formula (III-1).In one embodiment of the invention, the heteroatom or heteroatom group in Z31 comprises —CO— or —C(S)—.In one embodiment of the invention, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R44, R45, R46, R47, R48, R49, R31, R32, and R33 are selected from hydrogen or deuterium.In an embodiment for the compound represented by the above formula (III-2), one and only one of Z11, Z21 and Z31 is a group containing a double bond; the double bond is, for example, a double bond between C and O in —C(O)—, or a double bond between C and S in —C(S)—; further preferably, Z11, Z21 and Z31 are different from each other, or two groups not containing the double bond in Z11, Z21 and Z31 are the same and the two same groups contain —O—, —NH—, —S—, or —Se—, preferably, —O—; still further preferably, Z11, Z21 and Z31 each independently have a molecular weight of 14.0-107.1, preferably 14.0-60; preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60; still more preferably, Z11, Z21 and Z31 are selected from —CH2—, —CD2—, —CH2CH2—, —CD2CH2—, —C(O)—, —CH2C(O)—, —NHC(O)—, —OC(O)—, —CH2CH2O—, —OCH2C(O)—, —CH2OC(O)—, —CH2CH2CH2O—, and —S—C(O)—.The invention also provides a compound represented by the following Formula (III-1-1) or Formula (III-2-1), or a pharmaceutically acceptable salt thereof:wherein, W1, W2, W3, Z11, Z12, Z21, Z22, Z31, Z32, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R44, R45, R46, R47, R48, R49, R31, R32, and R33 are defined as in the compound of Formula (I), Formula (I-1-P1), Formula (I-1-P2), Formula (I-1-P3), Formula (I-1-P4), Formula (III), Formula (III-1) or Formula (III-2).The invention also provides a compound represented by the following Formula (III-A), or a pharmaceutically acceptable salt thereof:wherein, L3 is defined as in the compound of Formula (I), Formula (I-1-P1), Formula (I-1-P2), Formula (I-1-P3), Formula (I-1-P4), Formula (III) or Formula (III-1).In one embodiment of the invention, L3 is selected from —C1-6alkylene-, —C2-6alkynylene-, -methylene-phenyl-phenyl-methylene-, -methylene-6-membered heteroaryl-6-membered heteroaryl-methylene-(e.g., -methylene-pyridinyl-pyridinyl-methylene-), andwherein the alkylene, methylene, and alkynylene are optionally substituted by one or more substituents independently selected from halogen, oxo, —CN, —OH, and —NH2; wherein the aryl and heteroaryl are optionally substituted by one or more substituents independently selected from halogen, —CN, C1-3alkyl, and C1-3 alkoxy; * represents the connecting end with N.In one embodiment of the invention, the ring W3 is selected from phenyl, naphthyl, 8-10-membered bicyclic heteroaryl, and C8-10bicycloalkyl; wherein the phenyl, naphthyl, heteroaryl, and cycloalkyl are optionally substituted by one or more substituents independently selected from halogen, —CN, C1-3alkyl, and C1-3alkoxy.In one embodiment of the invention, the ring W3 is selected from phenyl, naphthyl, 5-membered / 5-membered fused heteroaryl, 5-membered / 6-membered fused heteroaryl, 6-membered / 5-membered fused heteroaryl, 6-membered / 6-membered fused heteroaryl, 4-membered / 6-membered spirocycloalkyl, and 6-membered / 4-membered spirocycloalkyl; wherein the phenyl, naphthyl, fused heteroaryl, and spirocycloalkyl are optionally substituted by one or more substituents independently selected from F, Cl, Br, methyl, ethyl, methoxy, and ethoxy.In one embodiment of the invention, W3 is selected fromIn one embodiment of the invention, each of Z31 and Z32 is independently selected from —C1-3alkylene-, —C1-3oxaalkylene-, —C1-3thiaalkylene-, and —C1-3azaalkylene-; preferably, each of Z31 and Z32 is independently selected from —C1-2alkylene-, —C1-2oxaalkylene-, —C1-2thiaalkylene-, and —C1-2azaalkylene-; wherein the alkylene, oxaalkylene, thiaalkylene, and azaalkylene are optionally substituted by one or more substituents independently selected from deuterium and oxo.In one embodiment of the invention, each of Z31 and Z32 is independently selected from —CD2—, —C1-2alkylene-, —OC1-2alkylene-, —C(O)—, —C1-2alkylene-C(O)—, —OC1-2alkylene-C(O)—, —NH—C1-2alkylene-C(O)—, —S—C1-2alkylene-C(O)—, and —O—C1-2alkylene-C(O)—C1-2alkylene-.In one embodiment of the invention, each of Z31 and Z32 is independently selected from —C1-3alkylene-and —C1-3oxaalkylene-; wherein the alkylene and oxaalkylene are optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, methyl, and methoxy.In one embodiment of the invention, each of Z31 and Z32 is independently selected from —C1-3alkylene-; wherein the alkylene is optionally substituted by one or more substituents independently selected from deuterium and oxo.In one embodiment of the invention, each of Z31 and Z32 is independently selected from methylene, ethylene, —CD2—,In one embodiment of the invention, L3 is selected from* represents the connecting end with N.The invention also provides a compound represented by the following Formula (III-A′), or a pharmaceutically acceptable salt thereof:wherein, L3 is defined as in the compound of Formula (I), Formula (I-1-P1), Formula (I-1-P2), Formula (I-1-P3), Formula (I-1-P4), Formula (III), Formula (III-1) or Formula (III-A).The invention also provides a compound represented by the following Formula (III-B), or a pharmaceutically acceptable salt thereof:wherein, L1 and L2 are defined as in the compound of Formula (I), Formula (I-1-P1), Formula (I-1-P2), Formula (I-1-P3), Formula (I-1-P4), Formula (III) or Formula (III-1).In one embodiment of the invention, L1 isand * represents the connecting end with N.In one embodiment of the invention, L2 isand * represents the connecting end with N.In one embodiment of the invention, each of rings W1 and W2 is independently selected from C6-12aryl and 5-12-membered heteroaryl; wherein the aryl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, C1-3alkyl, and C1-3alkoxy.In one embodiment of the invention, each of rings W1 and W2 is independently selected from phenyl, C8-12aryl, and 7-12-membered heteroaryl; wherein the phenyl, aryl, and heteroaryl are optionally substituted by one or more substituents independently selected from halogen, —CN, methyl, and methoxy.In one embodiment of the invention, each of rings W1 and W2 is independently selected from phenyl, naphthyl, and 8-10-membered bicyclic heteroaryl; wherein the phenyl, naphthyl, and heteroaryl are optionally substituted by one or more substituents independently selected from halogen, —CN, C1-3alkyl, and C1-3alkoxy.In one embodiment of the invention, each of rings W1 and W2 is independently selected from phenyl, naphthyl, 5-membered / 5-membered fused heteroaryl, 5-membered / 6-membered fused heteroaryl, 6-membered / 5-membered fused heteroaryl, and 6-membered / 6-membered fused heteroaryl; wherein the phenyl, naphthyl, and fused heteroaryl are optionally substituted by one or more substituents independently selected from F, Cl, Br, —CN, methyl, ethyl, methoxy, and ethoxy.In one embodiment of the invention, each of rings W1 and W2 is independently selected fromIn one embodiment of the invention, each of Z11, Z12, Z21, and Z22 is independently selected from —C1-3alkylene-, —C1-3oxaalkylene-, —C1-3thiaalkylene-, and —C1-3azaalkylene-; wherein the alkylene, oxaalkylene, thiaalkylene, and azaalkylene are optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, methyl, and methoxy.In one embodiment of the invention, each of Z11, Z12, Z21, and Z22 is independently selected from —C1-3alkylene-and —C1-3oxaalkylene-; wherein the alkylene and oxaalkylene are optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, methyl, and methoxy.In one embodiment of the invention, each of Z11, Z12, Z21, and Z22 is independently selected from —C1-2alkylene-, —C1-2oxaalkylene-, —C1-2thiaalkylene-, and —C1-2azaalkylene-; wherein the alkylene, oxaalkylene, thiaalkylene, and azaalkylene are optionally substituted by one or more substituents independently selected from deuterium, halogen, oxo, —CN, —OH, —NH2, methyl, and methoxy.In one embodiment of the invention, each of Z11, Z12, Z21, and Z22 is independently selected from methylene.In a preferred embodiment of the invention, each of Z11, Z12, Z21, and Z22 is independently selected from methylene,For example, L1 and L2 are groups containing Z11 and Z21 respectively, one and only one of Z11 and Z21 is a group containing a double bond; the double bond is, for example, a double bond between C and O in —C(O)—, or a double bond between C and S in —C(S)—; preferably, the double bond is for example a double bond between C and O in —C(O)—; further preferably, neither Z11 nor Z21 is methylene, or a group not containing the double bond of Z11 and Z21 contains —O—, —NH—, —S—, or —Se—, preferably, —O—; still further preferably, Z11 and Z21 each independently have a molecular weight of 14.0-107.1, preferably 14.0-60; preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60; still more preferably, Z11, Z21 and Z31 are selected from —CH2—, —CD2—, —CH2CH2—, —CD2CH2—, —C(O)—, —CH2C(O)—, —NHC(O)—, —OC(O)—, —CH2CH2O—, —OCH2C(O)—, —CH2OC(O)—, —CH2CH2CH2O—, and —S—C(O)—.In one embodiment of the invention, each of L1 and L2 is independently selected from* represents the connecting end with N.The invention also provides a compound represented by the following Formula (III-B′) or Formula (III-B′-1), or a pharmaceutically acceptable salt thereof:wherein, L1 and L2 are defined as in the compound of Formula (I), Formula (I-1-P1), Formula (I-1-P2), Formula (I-1-P3), Formula (I-1-P4), Formula (III), Formula (III-1) or Formula (III-B).For example, L1 and L2 are groups containing Z11 and Z21 respectively, one and only one of Z11 and Z21 is a group containing a double bond; the double bond is, for example, a double bond between C and O in —C(O)—, or a double bond between C and S in —C(S)—; further preferably, neither Z11 nor Z21 is methylene, or a group not containing the double bond of Z11 and Z21 contains —O—, —NH—, —S—, or —Se—, preferably, —O—; still further preferably, Z11 and Z21 each independently have a molecular weight of 14.0-107.1, preferably 14.0-60; preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60; still more preferably, Z11, Z21 and Z31 are selected from —CH2—, —CD2—, —CH2CH2—, —CD2CH2—, —C(O)—, —CH2C(O)—, —NHC(O)—, —OC(O)—, —CH2CH2O—, —OCH2C(O)—, —CH2OC(O)—, —CH2CH2CH2O—, and —S—C(O)—.The invention also provides a compound represented by the following Formula (III-C), or a pharmaceutically acceptable salt thereof:wherein, W1, W2, and W3 are defined as in compound of Formula (I), Formula (I-1-P1), Formula (I-1-P2), Formula (I-1-P3), Formula (I-1-P4), Formula (III) or Formula (III-1).In one embodiment of the invention, each of rings W1, W2 and W3 is independently selected from phenyl, naphthyl, 8-10-membered bicyclic heteroaryl, and 5-6-membered monocyclic heteroaryl; wherein the phenyl, naphthyl, and heteroaryl are optionally substituted by one or more substituents independently selected from halogen, C1-3alkyl, and C1-3alkoxy.In one embodiment of the invention, each of rings W1, W2, and W3 is independently selected fromThe invention also provides a compound represented by the following Formula (III-C′), or a pharmaceutically acceptable salt thereof:wherein, W1, W2, and W3 are defined as in the compound of Formula (I), Formula (I-1-P1), Formula (I-1-P2), Formula (I-1-P3), Formula (I-1-P4), Formula (III), Formula (III-1) or Formula (III-C).The invention also provides a compound represented by the following Formula (III-D), or a pharmaceutically acceptable salt thereof:wherein, W1, W2, and W3 are defined as in compound of Formula (I), Formula (I-1-P1), Formula (I-1-P2), Formula (I-1-P3), Formula (I-1-P4), Formula (III) or Formula (III-1).In one embodiment of the invention, each of rings W1, W2, and W3 is independently selected from phenyl, naphthyl, and 8-10-membered bicyclic heteroaryl groups; wherein the phenyl, naphthyl, and heteroaryl are optionally substituted by one or more substituents independently selected from halogen, C1-3alkyl, and C1-3alkoxy.In one embodiment of the invention, each of rings W1, W2, and W3 is independently selected from phenyl and 9-10-membered bicyclic heteroaryl; wherein the heteroatoms in the heteroaryl are independently selected from oxygen or N, and the number of heteroatoms is 1 or 2; wherein the phenyl and heteroaryl are optionally substituted by one or more substituents independently selected from F, C1, methyl, and methoxy.In one embodiment of the invention, each of rings W1, W2, and W3 is independently selected fromThe invention also provides a compound represented by the following Formula (III-D′), or a pharmaceutically acceptable salt thereof:wherein, W1, W2, and W3 are defined as in the compound of Formula (I), Formula (I-1-P1), Formula (I-1-P2), Formula (I-1-P3), Formula (I-1-P4), Formula (III), Formula (III-1) or Formula (III-D).The invention also provides a compound represented by the following Formula (III-E), or a pharmaceutically acceptable salt thereof:wherein, W1, W2, and W3 are defined as in the compound of Formula (I), Formula (I-1-P1), Formula (I-1-P2), Formula (I-1-P3), Formula (I-1-P4), Formula (III) or Formula (III-1).In one embodiment of the invention, each of rings W1, W2, and W3 is independently selected from phenyl, naphthyl, and 8-10-membered bicyclic heteroaryl groups; wherein the phenyl, naphthyl, and heteroaryl are optionally substituted by one or more substituents independently selected from halogen, C1-3alkyl, and C1-3alkoxy.In one embodiment of the invention, each of rings W1, W2, and W3 is independently selected from 9-membered bicyclic heteroaryl; wherein the heteroatoms in the heteroaryl are independently selected from O or N, and the number of heteroatoms is 1 or 2.In one embodiment of the invention, each of rings W1, W2, and W3 is independently selected fromThe invention also provides a compound represented by the following Formula (III-E′), or a pharmaceutically acceptable salt thereof:wherein, W1, W2, and W3 are defined as in the compound of Formula (I), Formula (I-1-P1), Formula (I-1-P2), Formula (I-1-P3), Formula (I-1-P4), Formula (III), Formula (III-1) or Formula (III-E).The invention also provides a compound represented by the following Formula (IV), or a pharmaceutically acceptable salt thereof:wherein, each of R3, R4, R9, R10, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, and R26 is independently selected from H and deuterium, and at least one of R3, R4, R9, R10, and R13-R26 is deuterium.The invention also provides a compound represented by the following Formula (A), or a pharmaceutically acceptable salt thereof:wherein, each of R3, R4, R9, R10, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, and R26 is independently selected from H and deuterium, and at least one of R3, R4, R9, R10, and R13-R26 is deuterium;each of RA, RB, and RC are independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, —C1-3alkylene-O—C1-6alkyl, and —C1-3alkylene-O—C(O)—C1-6alkyl, wherein the alkyl, alkenyl, alkoxy, and alkylene are optionally substituted by one or more substituents independently selected from deuterium, halogen, —OH, —NH2, —CN, oxo, C1-3alkyl, and C1-3alkoxy.In one embodiment of the invention, each of RA, RB, and RC is independently selected from C1-6alkyl, C1-6alkoxy, —C1-2alkylene-O—C1-4alkyl, —C1-2alkylene-O—C(O)—C1-4alkyl, wherein the alkyl, C1-6alkoxy, and alkylene are optionally substituted by one or more substituents independently selected from deuterium, F, Cl, Br, —OH, —NH2, —CN, oxo, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, and isopropoxy.In one embodiment of the invention, each of RA, RB, and RC is independently selected from C1-3alkyl, -methylene-O—C1-4alkyl, and -methylene-O—C(O)—C1-3alkyl, wherein the methylene and alkyl are optionally substituted by one or more substituents independently selected from methyl, ethyl, n-propyl, and isopropyl.In one embodiment of the invention, each of RA, RB, and RC is independently selected from methyl, ethyl, and —CH2—OC(O)—CH(CH3)2.The invention also provides a compound represented by the following Formula (B), Formula (B-1), Formula (C), Formula (C-1), Formula (D), or Formula (D-1), or a pharmaceutically acceptable salt thereof:wherein, Z11, Z21, Z31, R31, R32, R33, h1, h2, h3, h4, h5, and h6 are respectively defined as in the compound of Formula (I), Formula (I-1-P1), Formula (I-1-P2), Formula (I-1-P3), Formula (I-1-P4), Formula (III), Formula (III-1) or Formula (III-B); each of X and X2 is independently selected from O, CH2, NH, and S, and Se, X1 is independently selected from O and S, each of n, n1, and n3 are independently 0 or 1, and n2 is independently 0, 1, 2, or 3; each of Z12, Z22, and Z32 is independently selected from methylene, ethylene, and —CD2—, or selected from methylene and ethylene;each of rings W1, W2, and W3 is independently selected from phenyl and 5-6 membered monocyclic heteroaryl; wherein the phenyl and heteroaryl are optionally substituted by one or more substituents independently selected from deuterium, halogen, —CN, —OH, —NH2, —CHO, C1-3alkyl, C1-3alkoxy, —N(C1-3alkyl)2, —NH(C1-3alkyl), and —C(O)C1-3alkyl; wherein the heteroatom in the heteroaryl is O, N, or S, and the number of heteroatoms is 1 or 2.In one embodiment of the invention, each of Z12, Z22 and Z32 is independently selected from methylene, and —CD2—.In one embodiment of the invention, Z11 is —CD2—.In one embodiment of the invention, Z11 is independently selected from —C1-3alkylene-, —OC1-3alkylene-, —NH—C1-3alkylene-, —S—C1-3alkylene-, —Se—C1-3alkylene-, and —C1-2alkylene-O—C1-3alkylene-; preferably, Z11 is independently selected from —C1-3alkylene- and —OC1-3alkylene-; preferably, Z11 is independently selected from methylene, ethylene, methylene oxide, and ethylene oxide; preferably, Z11 is independently selected from methylene, and —CD2—; preferably, Z11 is independently selected from methylene.In one embodiment of the invention, Z21 is —CD2—.In one embodiment of the invention, Z21 is independently selected from —C1-3alkylene-, —OC1-3alkylene-, —NH—C1-3alkylene-, —S—C1-3alkylene-, —Se—C1-3alkylene-, and —C1-2alkylene-O—C1-3alkylene-; it is preferably selected from —OC1-3alkylene-, —NH—C1-2alkylene-, —S—C1-2alkylene-, and —C1-2alkylene-O—C1-3alkylene-.In one embodiment of the invention, Z31 is independently selected from —C(O)—, —C1-3alkylene-C(O)—, —OC1-3alkylene-C(O)—, —NH—C1-3alkylene-C(O)—, —S—C1-3alkylene-C(O)—, —O—C1-2alkylene-C(O)—C1-3alkylene-, —C1-3alkylene-NH—C(O)—, —C1-3alkylene-O—C(O)—, —NH—C(O)—, —O—C(O)—, —S—C(O)—, and —C1-3alkylene-C(S)—; it is preferably selected from —C(O)—, —C1-2alkylene-C(O)—, —OC1-2alkylene-C(O)—, —NH—C(O)—, —O—C(O)—, and —S—C(O)—.In one embodiment of the invention, Z12, Z22, and Z32 are all methylene.In one embodiment of the invention, X2 is selected from O, NH, and S; preferably, X2 is O.

[0310] In one embodiment of the invention, n2 is 0 or 1, n3 is 0, and X2 is CH2.

[0311] In one embodiment of the invention, n2 is 2 or 3, n3 is 0, X2 is O, NH, or S; or n2 is 1 or 2, n3 is 1,

[0312] X2 is O, NH, or S; further preferably, n2 is 2 or 3, n3 is 0, X2 is O; or n2 is 2, n3 is 1, X2 is O.

[0313] In one embodiment of the invention, n2 is 2, n3 is 0, and X2 is O, NH, or S; preferably, n2 is 2, n3 is 0, and X2 is O.

[0314] In one embodiment of the invention, the sum of n2 and n3 is not more than 3 (specifically 0, 1, 2, and 3); preferably the sum of n2 and n3 is not more than 2 (specifically 0, 1, and 2); preferably the sum of n2 and n3 is 1 or 2 (i.e., n2 is 2 and n3 is 0; or n2 is 1 and n3 is 1; or n2 is 0 and n3 is 2).

[0315] In one embodiment of the invention, X1 is O.

[0316] In one embodiment of the invention, X is CH2.

[0317] In one embodiment of the invention, X is selected from O, CH2, NH, and S, n is 1, and n1 is 0; or X is O or CH2, n is 1, and n1 is 1.

[0318] In one embodiment of the invention, X1 is O, X is selected from O, CH2, NH, and S, n is 1, n1 is 0; or X1 is O, X is O or CH2, n is 1, n1 is 1; further preferably, X1 is O, X is selected from O, and CH2, n is 1, n1 is 0; or X1 is O, X is O or CH2, n is 1, n1 is 1; further preferably, X1 is O, X is selected from CH2, n is 1, n1 is 0.

[0319] In one embodiment of the invention, the sum of n and n1 is 0, 1, or 2; preferably the sum of n and n1 is 1 or 2 (i.e., n is 1 and n1 is 0; or n is 0 and n1 is 1; or nis 1 and n1 is 1; or n is 0 and n1 is 2; or n is 2 and n1 is 0); preferably the sum of n and n1 is 1 (i.e., nis 1 and n1 is 0; or nis 0 and n1 is 1). For example, in any of the above-mentioned Formula (B) and Formula (B-1), each of Z11 and Z21 is a group not containing a double bond; the double bond is, for example, a double bond between C and O in —C(O)—, or a double bond between C and S in —C(S)—; further preferably, Z11 and Z21 are identical or different, and at least one of Z11 and Z21 is a group containing —O—, —NH—, —S—, or —Se—, preferably, a group containing —O—, e.g. *—CH2O—, *—CH2CH2O—, * is the connecting end with N; still further preferably, Z11, Z21 and *—C(X1)—(CH2)n1—(X)n— each independently have a molecular weight of 14.0-107.1, preferably 14.0-60; preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60; still more preferably, Z11, Z21 and Z31 are selected from —CH2—, —CD2—, —CH2CH2—, —CD2CH2—, —C(O)—, —CH2C(O)—, —NHC(O)—, —OC(O)—, —CH2CH2O—, —OCH2C(O)—, —CH2OC(O)—, —CH2CH2CH2O—, and —S—C(O)—.

[0320] For example, in any of the above-mentioned Formula (B) and Formula (B-1), each of Z12, Z22 and Z32 is independently selected from methylene and —CD2—;

[0321] each of Z11 and Z21 is independently selected from —CD2—, —C1-3alkylene-(preferably —C1-2alkylene-), —OC1-3alkylene-* (preferably —OC1-2alkylene-*), —SC1-3alkylene-*, —NHC1-3alkylene-*, —Se—C1-3alkylene-*, and —CH2—O—C1-2alkylene-*, * is the connecting end with N;

[0322] X1 is O or S, X is selected from O, CH2, NH, and S, n is 1, n1 is 0; or X1 is O or S, X is O or CH2, n is 1, n1 is 1; or X1 is O or S, n is 0, n1 is 0.

[0323] For example, in any of the above-mentioned Formula (B) and Formula (B-1), each of Z12, Z22 and Z32 is independently selected from methylene, and —CD2—;

[0324] Z11 is independently selected from —CD2—, —CH2—, —CH2CH2—, —OCH2—*, and —OCH2CH2—*, * is the connecting end with N;

[0325] Z21 is independently selected from —OCH2CH2—*, —CH2OCH2CH2—*, and —OCH2CH2CH2—*, * is the connecting end with N;

[0326] X1 is O, X is selected from O, CH2, NH, and S, n is 1, n1 is 0; or X1 is O, X is O or CH2, n is 1, n1 is 1.

[0327] For example, in any of the above-mentioned Formula (B) and Formula (B-1), each of Z12, Z22 and Z32 is independently selected from methylene, and —CD2—; each of Zu and Z21 is independently selected from —CD2—, —C1-3alkylene-(preferably —C1-2alkylene-), —OC1-3alkylene-* (preferably —OC1-2alkylene-*), —SC1-3alkylene-*, —NHC1-3alkylene-*, —Se—C1-3alkylene-*, and —CH2—O—C1-2alkylene-*, * is the connecting end with N, X1 is O or S, X is selected from O, CH2, NH, and S, the sum of n and n1 is 0, 1, or 2; further preferably, Z21 is independently selected from —OCH2CH2—*, —CH2OCH2CH2—*, and —OCH2CH2CH2—*, * is the connecting end with N; further preferably, X1 is O, X is selected from O, CH2, NH, and S, the sum of n and n1 is 1, or 2.

[0328] For example, in any of the above-mentioned Formula (C) and Formula (C-1), one and only one of Z11 and Z31 is a group containing a double bond; the double bond is, for example, a double bond between C and O in —C(O)—, or a double bond between C and S in —C(S)—; further preferably, the group not containing a double bond of Z11 and Z31 is identical to or different from *—(CH2)n2—X2—(CH2)n3—(* represents the connecting end with N); still further preferably, Z11, —(CH2)n2—X2—(CH2)n3— and Z31 each independently have a molecular weight of 14.0-107.1, preferably 14.0-60; preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60; still more preferably, Z11, Z21 and Z31 are selected from —CH2—, —CD2—, —CH2CH2—, —CD2CH2—, —C(O)—, —CH2C(O)—, —NHC(O)—, —OC(O)—, —CH2CH2O—, —OCH2C(O)—, —CH2OC(O)—, —CH2CH2CH2O—, and —S—C(O)—.

[0329] For example, in any of the above-mentioned Formula (C) and Formula (C-1), each of Z12, Z22 and Z32 is independently selected from methylene, and —CD2—;

[0330] Z11 is independently selected from —CD2—, —C1-3alkylene-(preferably —C1-2alkylene-), —OC1-3alkylene-* (preferably —OC1-2alkylene-*), —SC1-2alkylene-*, —NHC1-2alkylene-*, —Se—C1-2alkylene-*, and —CH2—O—C1-2alkylene-*, * is the connecting end with N;

[0331] Z31 is independently selected from —C(O)—, —C1-3alkylene-C(O)—*, —OC1-2alkylene-C(O)—*, —NHCH2—C(O)—*, —SCH2—C(O)—*, —CH2—NHC(O)—*, —C1-2alkylene-O—C(O)—*, —NH—C(O)—*, —O—C(O)—*, —S—C(O)—*, and —C1-2alkylene-C(S)—*, * is the connecting end with N;

[0332] n2 is 2 or 3, n3 is 0, X2 is O, NH, or S; or n2 is 1 or 2, n3 is 1, X2 is O, NH, or S; or n2 is 0 or 1, n3 is 0, X2 is CH2.

[0333] For example, in any of the above-mentioned Formula (C) and Formula (C-1), each of Z12, Z22 and Z32 is independently selected from methylene, and —CD2—;

[0334] Z11 is independently selected from —CD2—, —CH2—, —CH2CH2—, —OCH2—*, and —OCH2CH2—*, * is the connecting end with N;

[0335] Z31 is independently selected from —C(O)—, —CH2CH2C(O)—*, —CH2C(O)—*, —OCH2C(O)—*, —NHC(O)—*, —OC(O)—*, and —SC(O)—*, * is the connecting end with N;

[0336] n2 is 2 or 3, n3 is 0, X2 is O; or n2 is 1 or 2, n3 is 1, X2 is O; or n2 is 0 or 1, n3 is 0, X2 is CH2.

[0337] For example, in any of the above-mentioned Formula (C) and Formula (C-1), each of Z12, Z22 and Z32 is independently selected from methylene, and —CD2—; Z11 is independently selected from —CD2—, —C1-3alkylene-(preferably —C1-2alkylene-), —OC1-3alkylene-* (preferably —OC1-2alkylene-*), —SC1-2alkylene-*, —NHC1-2alkylene-*, —Se—C1-2alkylene-*, and —CH2—O—C1-2alkylene-*, Z31 is independently selected from —C(O)—, —C1-3alkylene-C(O)—*, —OC1-2alkylene-C(O)—*, —NHCH2—C(O)—*, —SCH2—C(O)—*, —CH2—NHC(O)—*, —C1-2alkylene-O—C(O)—*, —NH—C(O)—*, —O—C(O)—*, —S—C(O)—*, and —C1-2alkylene-C(S)—*, * is the connecting end with N; further preferably, Z11 is independently selected from —CD2—, —CH2—, —CH2CH2—, and —OCH2CH2—*, * is the connecting end with N; further preferably, Z31 is independently selected from —CH2CH2C(O)—*, —CH2C(O)—*, —OCH2C(O)—*, —NHC(O)—*, —OC(O)—*, and —SC(O)—*, * is the connecting end with N; further preferably, X2 is O, NH, S, or Se, the sum of n2 and n3 is 1, 2, or 3; further preferably, X2 is O, the sum of n2 and n3 is 2, or 3.

[0338] For example, in any of the above-mentioned Formula (D) and Formula (D-1), Z11 is a group not containing a double bond; the double bond is, for example, a double bond between C and O in —C(O)—, or a double bond between C and S in —C(S)—; further preferably, Z11 is identical to or different from *—(CH2)n2—X2—(CH2)n3— (* represents the connecting end with N); still further preferably, Z11, —C(X1)—(CH2)n1—(X)n— and —(CH2)n2—X2—(CH2)n3— each independently have a molecular weight of 14.0-107.1, preferably 14.0-60; preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60; still more preferably, Z11, Z21 and Z31 are selected from —CH2—, —CD2—, —CH2CH2—, —CD2CH2—, —C(O)—, —CH2C(O)—, —NHC(O)—, —OC(O)—, —CH2CH2O—, —OCH2C(O)—, —CH2OC(O)—, —CH2CH2CH2O—, and —S—C(O)—.

[0339] For example, in any of the above-mentioned Formula (D) and Formula (D-1), each of Z12, Z22 and Z32 is independently selected from methylene, and —CD2—;

[0340] Z11 is independently selected from —CD2—, —C1-2alkylene-, —OC1-2alkylene-*, —SC1-2alkylene-*, —NHC1-zalkylene-*, —Se—C1-2alkylene-*, and —CH2—O—C1-2alkylene-*, * is the connecting end with N;

[0341] n2 is 2 or 3, n3 is 0, X2 is O, NH, or S; or n2 is 1 or 2, n3 is 1, X2 is O, NH, or S; or n2 is 0 or 1, n3 is 0, X2 is CH2;

[0342] X1 is O or S, X is selected from O, CH2, NH, and S, n is 1, n1 is 0; or X1 is O or S, X is O or CH2, n is 1, n1 is 1.

[0343] For example, in any of the above-mentioned Formula (D) and Formula (D-1), each of Z12, Z22 and Z32 is independently selected from methylene, and —CD2—;

[0344] Z11 is independently selected from —CD2—, —CH2—, —CH2CH2—, —OCH2—*, and —OCH2CH2—*, * is the connecting end with N;

[0345] n2 is 2 or 3, n3 is 0, X2 is O; or n2 is 1 or 2, n3 is 1, X2 is O; or n2 is 0 or 1, n3 is 0, X2 is CH2;

[0346] X1 is O, X is selected from O, CH2, NH, and S, n is 1, n1 is 0; or X1 is O, X is O or CH2, n is 1, n1 is 1.

[0347] For example, in any of the above-mentioned Formula (D) and Formula (D-1), each of Z12, Z22 and Z32 is independently selected from methylene, and —CD2—;

[0348] Z11 is independently selected from —CD2—, —CH2—, —CH2CH2—, and —OCH2CH2—*, * is the connecting end with N;

[0349] n2 is 2 or 3, n3 is 0, X2 is O; or n2 is 2, n3 is 1, X2 is O;

[0350] X1 is O, X is selected from O, CH2, NH, and S, n is 1, n1 is 0.

[0351] For example, in any of the above-mentioned Formula (D) and Formula (D-1), each of Z12, Z22 and Z32 is independently selected from methylene, and —CD2—; Z11 is independently selected from —CD2—, —C1-2alkylene-, —OC1-2alkylene-*, —SC1-2alkylene-*, —NHC1-2alkylene-*, —Se—C1-2alkylene-*, and —CH2—O—C1-2alkylene-*, * is the connecting end with N; X2 is O, NH, S, or Se, the sum of n2 and n3 is 1, 2, or 3; X1 is O or S, X is selected from O, CH2, NH, and S, the sum of n and n1 is 0, 1, or 2; further preferably, Z11 is independently selected from —CD2—, —CH2—, —CH2CH2—, and —OCH2CH2—*, * is the connecting end with N; further preferably, X2 is O, the sum of n2 and n3 is 2, or 3; X1 is O, X is selected from O, CH2, NH, and S, the sum of n and n1 is 1, or 2.

[0352] In one embodiment of the invention, each of ring W1, W2, and W3 is independently selected from the following optionally substituted groups:wherein “optionally substituted” refers to unsubstituted or substituted by one or more substituents independently selected from deuterium, halogen, —CN, —OH, —NH2, —CHO, C1-3alkyl, C1-3alkoxy, —N(C1-3alkyl)2, —NH(C1-3alkyl), and —C(O)C1-3alkyl.In one embodiment of the invention, each of rings W1, W2, W3 is independently selected from the following groups optionally substituted:wherein “optionally substituted” refers to unsubstituted or substituted by one or more substituents independently selected from deuterium, F, Cl, Br, methyl, ethyl, methoxy, and ethoxy.The invention also provides a compound represented by the following Formula (B-2), Formula (B-3), Formula (C-2), Formula (C-3), Formula (D-2), and Formula (D-3), or a pharmaceutically acceptable salt thereof:wherein, Z11, Z21, Z12, Z22, Z32, X, X1, n, n1, and rings W1, W2, and W3 in Formula (B-2) and Formula (B-3) are defined as in the compound of Formula (B); Z11, Z31, Z12, Z22, Z32, X2, n2, n3, and rings W1, W2, and W3 in Formula (C-2) and Formula (C-3) are defined as in the compound of Formula (C); andZ11, Z12, Z22, Z32, X, X1, X2, n, n1, n2, n3, and rings W1, W2, and W3 in Formula (D-2) and Formula (D-3) are defined as in the compound of Formula (D).For example, in any of the above-mentioned Formula (B-2) and Formula (B-3), each of Z11 and Z21 is a group not containing a double bond; the double bond is, for example, a double bond between C and O in —C(O)—, or a double bond between C and S in —C(S)—; further preferably, Z11 and Z21 are identical or different, and at least one of Z11 and Z21 is a group containing —O—, —NH—, —S—, or —Se—, preferably, a group containing —O—, e.g. *—CH2O—, *—CH2CH2O—, * is the connecting end with N; still further preferably, Z11, Z21 and *—C(X1)—(CH2)n1—(X)n— each independently have a molecular weight of 14.0-107.1, preferably 14.0-60; preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60; still more preferably, Z11, Z21 and Z31 are selected from —CH2—, —CD2—, —CH2CH2—, —CD2CH2—, —C(O)—, —CH2C(O)—, —NHC(O)—, —OC(O)—, —CH2CH2O—, —OCH2C(O)—, —CH2OC(O)—, —CH2CH2CH2O—, and —S—C(O)—.

[0358] For example, in any of the above-mentioned Formula (C-2) and Formula (C-3), one and only one of Z11 and Z31 is a group containing a double bond; the double bond is, for example, a double bond between C and O in —C(O)—, or a double bond between C and S in —C(S)—; further preferably, the group not containing a double bond of Z11 and Z31 is identical to or different from *—(CH2)n2—X2—(CH2)n3— (* represents the connecting end with N); still further preferably, Z11, —(CH2)n2—X2—(CH2)n3— and Z31 each independently have a molecular weight of 14.0-107.1, preferably 14.0-60; preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60; still more preferably, Z11, Z21 and Z31 are selected from —CH2—, —CD2—, —CH2CH2—, —CD2CH2—, —C(O)—, —CH2C(O)—, —NHC(O)—, —OC(O)—, —CH2CH2O—, —OCH2C(O)—, —CH2OC(O)—, —CH2CH2CH2O—, and —S—C(O)—.

[0359] For example, in any of the above-mentioned Formula (D-2) and Formula (D-3), Z11 is a group not containing a double bond; the double bond is, for example, a double bond between C and O in —C(O)—, or a double bond between C and S in —C(S)—; further preferably, Z11 is identical to or different from *—(CH2)n2—X2—(CH2)n3— (* represents the connecting end with N); still further preferably, Z11, —C(X1)—(CH2)n1—(X)n— and —(CH2)n2—X2—(CH2)n3— each independently have a molecular weight of 14.0-107.1, preferably 14.0-60; preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60; still more preferably, Z11, Z21 and Z31 are selected from —CH2—, —CD2—, —CH2CH2—, —CD2CH2—, —C(O)—, —CH2C(O)—, —NHC(O)—, —OC(O)—, —CH2CH2O—, —OCH2C(O)—, —CH2OC(O)—, —CH2CH2CH2O—, and —S—C(O)—.

[0360] The invention also provides a compound represented by the following Formula (E), Formula (E-1) and Formula (F), or a pharmaceutically acceptable salt thereof:wherein, L1 and L2 are defined as in the compound of Formula (I), Formula (I-1), Formula (III), Formula (III-1), Formula (III-B), Formula (B), Formula (C) or Formula (D), X is O, CH2 or NH, Ra is deuterium, halogen, —CN, —OH, —NH2, —CHO, C1-3alkyl, C1-3alkoxy, —N(C1-3alkyl)2, —NH(C1-3alkyl), and —C(O)C1-3alkyl, n1 is 0 or 1, m is 0 or 1, and n is 0 or 1; R23 and R24 are each independently selected from H, and deuterium.

[0362] For example, in any of the above-mentioned Formula (E) and Formula (E-1), L1 and L2 are groups containing Z11 and Z21 respectively, and each of Z11 and Z21 is a group not containing a double bond; the double bond is, for example, a double bond between C and O in —C(O)—, or a double bond between C and S in —C(S)—; further preferably, Z11 and Z21 are identical or different; still further preferably, Z11, Z21 and —C(O)—(CH2)n1—(X)n— each independently have a molecular weight of 14.0-107.1, preferably 14.0-60; preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60; still more preferably, Z11, Z21 and Z31 are selected from —CH2—, —CD2—, —CH2CH2—, —CD2CH2—, —C(O)—, —CH2C(O)—, —NHC(O)—, —OC(O)—, —CH2CH2O—, —OCH2C(O)—, —CH2OC(O)—, —CH2CH2CH2O—, and —S—C(O)—.

[0363] For example, in the above-mentioned Formula (F), L1 and L2 are groups containing Z11 and Z21 respectively, and

[0364] one and only one of Z11 and Z21 is a group containing a double bond; the double bond is, for example, a double bond between C and O in —C(O)—, or a double bond between C and S in —C(S)—; further preferably, the group not containing a double bond of Z11 and Z21 is identical to or different from *—(CH2) 2—O— (*represents the connecting end with N); still further preferably, Z11 and Z21 each independently have a molecular weight of 14.0-107.1, preferably 14.0-60; preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60; still more preferably, Z11, Z21 and Z31 are selected from —CH2—, —CD2—, —CH2CH2—, —CD2CH2—, —C(O)—, —CH2C(O)—, —NHC(O)—, —OC(O)—, —CH2CH2O—, —OCH2C(O)—, —CH2OC(O)—, —CH2CH2CH2O—, and —S—C(O)—.

[0365] In one embodiment of the invention, Ra is F, C1, methyl, ethyl, methoxy and ethoxy; preferably Ra is F.

[0366] In one embodiment of the invention, m is 1.

[0367] In one embodiment of the invention, X is CH2.

[0368] In one embodiment of the invention, X is selected from O, CH2, NH, and S, n is 1, and n1 is 0; or X is O or CH2, n is 1, and n1 is 1.

[0369] In one embodiment of the invention, the sum of n and n1 is 0, 1, or 2; preferably the sum of n and n1 is 1 or 2 (i.e., n is 1 and n1 is 0; or n is 0 and n1 is 1; or nis 1 and n1 is 1; or n is 0 and n1 is 2; or n is 2 and n1 is 0); preferably the sum of n and n1 is 1 (i.e., nis 1 and n1 is 0; or n is 0 and n1 is 1). For example, in any of the above-mentioned Formula (E), Formula (E-1), and Formula (F), Ra is F, C1, methyl, ethyl, methoxy, or ethoxy, m is 1, X is selected from O, CH2, NH, and S, the sum of n and n1 is 0, 1, or 2.

[0370] further preferably, Ra is F, or methoxy, m is 1, X is selected from O, CH2, NH, and S, the sum of n and n1 is 1, or 2.

[0371] In one embodiment of the invention, L1 isL2 isand * represents the connecting end with N; each of rings W1 and W2 is independently selected fromthe phenyl is optionally substituted by one or more substituents independently selected from halogen and C1-3alkoxy (preferably F and methoxy).In one embodiment of the invention, each of Z11, Z12, Z21 and Z22 is independently selected from —C1-2alkylene-, —OC1-3alkyl-, —NH—C1-2alkylene-, —S—C1-2alkylene-, —C1-2alkylene-O—C1-2alkylene-, —C1-2alkylene-C(O)—, —OC1-2alkylene-C(O)—, —C1-2alkylene-NH—C(O)—, —C1-2alkylene-O—C(O)—, —NH—C(O)—, —NH—C1-2alkyl-C(O)—, —O—C(O)—, and —S—C(O)—.In one embodiment of the invention, each of Z11, Z12, Z21, and Z22 is independently selected from methylene, ethylene,In one embodiment of the invention, each of L1 and L2 is independently selected fromindicates the connecting end with N. The invention also provides a compound represented by the following Formula (E-2), Formula (E-3), Formula (E-4),Formula (F-1), and Formula (F-2), or a pharmaceutically acceptable salt thereof:wherein, L1, L2, X, m, n, n1, and Ra in Formula (E-2), Formula (E-3) and Formula (E-4) are defined as in Formula (E) and Formula (E-1);R23 and R24 in Formula (E-4) are defined as in Formula (E-1); andL1 and L2 in Formula (F-1) and Formula (F-2) are defined as in Formula (F).For example, in any of the above-mentioned Formula (E-2), Formula (E-3), and Formula (E-4), L1 and L2 are groups containing Z11 and Z21 respectively, and each of Z11 and Z21 is a group not containing a double bond; the double bond is, for example, a double bond between C and O in —C(O)—, or a double bond between C and S in —C(S)—; further preferably, Z11 and Z21 are identical or different; still further preferably, Z11, Z21 and —C(O)—(CH2)n1—(X)n— each independently have a molecular weight of 14.0-107.1, preferably 14.0-60; preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60; still more preferably, Z11, Z21 and Z31 are selected from —CH2—, —CD2—, —CH2CH2—, —CD2CH2—, —C(O)—, —CH2C(O)—, —NHC(O)—, —OC(O)—, —CH2CH2O—, —OCH2C(O)—, —CH2OC(O)—, —CH2CH2CH2O—, and —S—C(O)—.For example, in any of the above-mentioned Formula (F-1) and Formula (F-2), L1 and L2 are groups containing Z11 and Z21 respectively, and one and only one of Zu and Z21 is a group containing a double bond; the double bond is, for example, a double bond between C and O in —C(O)—, or a double bond between C and S in —C(S)—; further preferably, the group not containing a double bond of Z11 and Z21 is identical to or different from *—(CH2)2—O—(*represents the connecting end with N); still further preferably, Z11 and Z21 each independently have a molecular weight of 14.0-107.1, preferably 14.0-60; preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60; still more preferably, Z11, Z21 and Z31 are selected from —CH2—, —CD2—, —CH2CH2—, —CD2CH2—, —C(O)—, —CH2C(O)—, —NHC(O)—, —OC(O)—, —CH2CH2O—, —OCH2C(O)—, —CH2OC(O)—, —CH2CH2CH2O—, and —S—C(O)—.The invention also provides a compound represented by the following Formula (G), or a pharmaceutically acceptable salt thereof:wherein, X, X1, X2, n, n1, n2, and n3 are defined as in the compounds of Formula (I), Formula (I-1-P1), Formula (I-1-P2), Formula (I-1-P3), Formula (I-1-P4), Formula (III), Formula (III-1), Formula (III-B), Formula (B), Formula (C), or Formula (D), m is independently 0 or 1, n4 is 0, 1, 2, or 3, X3 is selected from O, S, CH2, and NH; or X3 is O, S, CH2, NH, or CD2, Ra is selected from deuterium, halogen, —CN, —OH, —NH2, —CHO, C1-3alkyl, C1-3alkoxy, —N(C1-3alkyl)2, —NH(C1-3alkyl), and —C(O)C1-3alkyl.In one embodiment of the invention, Ra is F, C1, methyl, ethyl, methoxy, ethoxy; preferably F and methoxy.

[0383] In one embodiment of the invention, m is 1.

[0384] In one embodiment of the invention, n4 is 0, 1, or 2, preferably 0 or 1 and more preferably 0.

[0385] In one embodiment of the invention, X3 is O or CH2; or X3 is O, CH2, or CD2.

[0386] In one embodiment of the invention, X3 is O and n4 is 2; or X3 is CH2 and n4 is 0 or 1; or X3 is CH2, or CD2, n4 is 0 or 1; further preferably, X3 is CH2, or CD2, n4 is 0.

[0387] For example, in the above-mentioned Formula (G), Ra is F, C1, methyl, ethyl, methoxy, or ethoxy; m is 1; X2 is O, NH, S, or Se, the sum of n2 and n3 is 1, 2, or 3; X1 is O or S, X is selected from O, CH2, NH, and S, the sum of n and n1 is 0, 1, or 2;

[0388] X3 is O, n4 is 2; or X3 is CH2, or CD2, n4 is 0 or 1.

[0389] further preferably, Ra is F, C1, or methoxy; m is 1; X2 is O, the sum of n2 and n3 is 2, or 3; X1 is O, X is selected from O, CH2, NH, and S, the sum of n and n1 is 1, or 2;

[0390] X3 is O, n4 is 2; or X3 is CH2, or CD2, n4 is 0 or 1.

[0391] For example, in the above-mentioned Formula (G), Ra is F, C1, methyl, ethyl, methoxy, or ethoxy; m is 1;

[0392] X3 is O, n4 is 2; or X3 is CH2, or CD2, n4 is 0 or 1;

[0393] n2 is 2 or 3, n3 is 0, X2 is O, NH, S; or n2 is 1 or 2, n3 is 1, X2 is O, NH, S; or n2 is 0 or 1, n3 is 0, X2 is CH2;

[0394] X1 is O or S, X is selected from O, CH2, NH, and S, n is 1, n1 is 0; or X1 is O or S, X is O or CH2, n is 1, n1 is 1.

[0395] For example, in the above-mentioned Formula (G), Ra is F, C1, or methoxy; m is 1;

[0396] X3 is O, n4 is 2; or X3 is CH2, or CD2, n4 is 0 or 1;

[0397] n2 is 2 or 3, n3 is 0, X2 is O; or n2 is 1 or 2, n3 is 1, X2 is O; or n2 is 0 or 1, n3 is 0, X2 is CH2;

[0398] X1 is O, X is selected from O, CH2, NH, and S, n is 1, n1 is 0; or X1 is O, X is O or CH2, n is 1, n1 is 1.

[0399] The invention also provides a compound represented by the following Formula (G-1) and Formula (G-2), or a pharmaceutically acceptable salt thereof:wherein, X, X1, X2, X3, n, n1, n2, n3, n4, m, and Ra are defined as in the compound of Formula (G). The invention also provides a compound represented by the following Formula (G-3) or Formula (G-4), or a pharmaceutically acceptable salt thereof:wherein, X, X1, X2, X3, n, n1, n2, n3, n4, m, and Ra are defined as in Formula (G), and R19, R20, R21, R22, R23, and R24 are each independently selected from hydrogen and deuterium.For example, in any of the above-mentioned Formula (G), Formula (G-1), Formula (G-2), Formula (G-3), and Formula (G-4), *—(CH2)n4—X3—, *—(CH2)n2—X2—(CH2)n3—, and *—C(X1)—(CH2)n1—(X)n— (* represents the connecting end with N) are identical to or different from each other, and they each independently have a molecular weight of 14.0-107.1, preferably 14.0-60; preferably about 14, about 16, about 28, about 30, about 42, about 43, about 44, about 46, about 58, or about 60; still more preferably, Z11, Z21 and Z31 are selected from —CH2—, —CD2—, —CH2CH2—, —CD2CH2—, —C(O)—, —CH2C(O)—, —NHC(O)—, —OC(O)—, —CH2CH2O—, —OCH2C(O)—, —CH2OC(O)—, —CH2CH2CH2O—, and —S—C(O)—.

[0403] The invention also provides a compound represented by the following Formula (H), or a pharmaceutically acceptable salt thereof:wherein, X, X1, X2, n, n1, n2, and n3 are defined as in the compound of Formula (I), Formula (I-1-P1), Formula (I-1-P2), Formula (I-1-P3), Formula (I-1-P4), Formula (III), Formula (III-1), Formula (III-B), Formula (B), Formula (C), Formula (D), or Formula (G), m is independently 0 or 1, n5 is 1, 2, 3 or 4, and Rª is selected from deuterium, halogen, —CN, —OH, —NH2, —CHO, C1-3alkyl, C1-3alkoxy, —N(C1-3alkyl)2, —NH(C1-3alkyl), and —C(O)C1-3 alkyl.

[0405] In one embodiment of the invention, Ra is F, C1, methyl, ethyl, methoxy, or ethoxy; preferably Ra is F or methoxy.

[0406] In one embodiment of the invention, m is 1.

[0407] In one embodiment of the invention, n5 is 1, 2, or 3, preferably 1 or 2 and more preferably 1.

[0408] The invention also provides a compound represented by the following Formula (H-1) and Formula (H-2), or a pharmaceutically acceptable salt thereof:wherein, X, X1, X2, n, n1, n2, n3, n5, m, and Ra are defined as in the compound of Formula (H).

[0410] The invention also provides a compound represented by the following Formula (H-3) and Formula (H-4), or a pharmaceutically acceptable salt thereof:wherein, X, X1, X2, n, n1, n2, n3, n5, m, and Ra are defined as in Formula (H), and R13, R14, R19, R20, R21, R22, R23, and R24 are each independently selected from hydrogen and deuterium.

[0412] The invention also provides a compound represented by Formula (D-c), Formula (D-f), Formula (D-g), or Formula (D-h) or a pharmaceutically acceptable salt thereof:wherein, Z11, Z12, Z22, Z32, X, X1, X2, n, n1, n2, n3, and rings W1, W2, and W3 are defined as in the compound of Formula (I), Formula (I-1-P1), Formula (I-1-P2), Formula (I-1-P3), Formula (I-1-P4), or Formula (D), each of Pg1 and Pg2 is independently a protecting group. Preferably, Pg1 is independently selected from tert-butyl, methyl, and benzyl, Pg2 is independently selected from tert-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (FMOC), and andbenzyloxycarbonyl (Cbz), preferably Boc.

[0414] Based on the common knowledge in the field, the above specific technical features can be combined arbitrarily to obtain various preferred embodiments of the invention.

[0415] In one embodiment of the invention, the compounds of the invention or a pharmaceutically acceptable salt thereof are selected from:Comp.No.Structure 1-a 3,3′-((azanediylbis(methylene))bis(benzofuran- 3,5-diyl))bis(2-(pyrrolidin-3-yl)propanoic acid) 2-a 3,3′-((((3-fluoro-5- methoxybenzyl)azanediyl)bis(methylene))bis (benzofuran-3,5-diyl))bis(2-(pyrrolidin-3- yl)propanoic acid) 3-a 3,3′-((((pyridin-3- ylmethyl)azanediyl)bis(methylene))bis(benzo [b]thiophene-3,5-diyl))bis(2-(pyrrolidin-3- yl)propanoic acid) 4-a 3,3′-((((4- (aminomethyl)benzyl)azanediyl)bis(methylene)) bis(1H-indole-3,5-diyl))bis(2-(pyrrolidin-3- yl)propanoic acid) 5-a 3,3′-((((5-amino-5- carboxypentyl)azanediyl)bis(methylene))bis (5-fluoro-3,1-phenylene))bis(2-(pyrrolidin- 3-yl)propanoic acid) 6-a 3,3′-(((((5-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzofuran-3- yl)methyl)azanediyl)bis(methylene))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid) 7-a 3,3′-(((((5-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzofuran-2- yl)methyl)azanediyl)bis(methylene))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid) 8-a 3,3′-(((((4-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzofuran-2- yl)methyl)azanediyl)bis(methylene))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid) 9-a 3,3′-(((((2-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzofuran-7- yl)methyl)azanediyl)bis(methylene))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid) 10-a 3,3′-(((((5-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzo[b]thiophen-3- yl)methyl)azanediyl)bis(methylene))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid) 11-a 3,3′-(((((6-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzo[b]thiophen-2- yl)methyl)azanediyl)bis(methylene))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid) 12-a 3,3′-((((3-(2-carboxy-2-(pyrrolidin-3-yl)ethyl)-5- fluorobenzoyl)azanediyl)bis(methylene))bis(3, 1-phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid) 13-a 3,3′-((((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)azanediyl)bis(carbonyl))bis (5-fluoro-3,1-phenylene))bis(2-(pyrrolidin-3- yl)propanoic acid) 14-a 3,3′-(((((5-(2-carboxy-2-(pyrrolidin-3-yl)ethyl)- 1H-indol-3- yl)methyl)azanediyl)bis(methylene))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid) 15-a 3,3′-(((((5-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)-1H-indazol-3- yl)methyl)azanediyl)bis(methylene))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid) 16-a 3,3′-(((((5-(2-carboxy-2-(pyrrolidin-3-yl)ethyl)- 1H-pyrazolo[4,3-b]pyridin-3- yl)methyl)azanediyl)bis(methylene))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid) 17-a 3,3′-(((((5-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)-1H-benzo[d]imidazol-2- yl)methyl)azanediyl)bis(methylene))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid) 18-a 3,3′-(((((2-(2-carboxy-2-(pyrrolidin-3-yl)ethyl)- 1H-benzo[d]imidazol-7- yl)methyl)azanediyl)bis(methylene))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid) 19-a 3,3′-(((((2-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)-1-methyl-1H-benzo[d]imidazol-7- yl)methyl)azanediyl)bis(methylene))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid) 20-a 3,3′-(((((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)pyrrolo[3,4-b]pyrrol-4- yl)methyl)azanediyl)bis(methylene))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid) 21-a 3,3′-(((((7-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)naphthalen-1- yl)methyl)azanediyl)bis(methylene))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid) 22-a 3,3′-(((((6-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)quinolin-4- yl)methyl)azanediyl)bis(methylene))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid) 23-a 3,3′-(((((7-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)quinolin-2- yl)methyl)azanediyl)bis(methylene))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid) 24-a 3,3′-(((((2-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)quinazolin-8- yl)methyl)azanediyl)bis(methylene))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid) 25-a 3,3′-(((((3′-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)-[1,1′-biphenyl]-3- yl)methyl)azanediyl)bis(methylene))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid) 26-a 3,3′-(((((5′-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)-[3,3′-bipyridin]-5- yl)methyl)azanediyl)bis(methylene))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid) 27-a 3,3′-((((2-(4-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)-2H-isoindol-2- yl)ethyl)azanediyl)bis(methylene))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid) 28-a 3,3′-((((2-(4-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)-1H-indol-2- yl)ethyl)azanediyl)bis(methylene))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid) 29-a 3,3′-(((((2-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)spiro[3.5]nonan-7- yl)methyl)azanediyl)bis(methylene))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid) 30-a 3,3′-((((6-carboxy-6-(pyrrolidin-3- yl)hexyl)azanediyl)bis(methylene))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid) 31-a 3,3′-((((6-carboxy-6-(pyrrolidin-3-yl)hex-3- yn-1-yl)azanediyl)bis(methylene))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid) 32-a 3,3′-((((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)azanediyl)bis(methylene))bis (benzofuran-3,5-diyl))bis(2-(pyrrolidin-3- yl)propanoic acid) 33-a 3,3′-((((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)azanediyl)bis(methylene)) bis(benzofuran-2,5-diyl))bis(2-(pyrrolidin-3- yl)propanoic acid) 34-a 3,3′-((((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)azanediyl)bis(methylene))bis (benzo[b]thiophene-3,5-diyl))bis(2-(pyrrolidin-3- yl)propanoic acid) 35-a 3,3′-((((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)azanediyl)bis(methylene)) bis(1H-indole-3,5-diyl))bis(2-(pyrrolidin-3- yl)propanoic acid) 36-a 3,3′-((((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)azanediyl)bis(methylene))bis (1H-indazole-3,5-diyl))bis(2-(pyrrolidin-3- yl)propanoic acid) 37-a 3,3′-((((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)azanediyl)bis(methylene)) bis(1H-benzo[d]imidazole-2,5-diyl))bis(2- (pyrrolidin-3-yl)propanoic acid) 38-a 3,3′-((((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)azanediyl)bis(methylene))bis (1H-pyrazolo[4,3-b]pyridine-3,5-diyl))bis(2- (pyrrolidin-3-yl)propanoic acid) 39-a 3,3′-((((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)azanediyl)bis(methylene)) bis(benzofuran-7,2-diyl))bis(2-(pyrrolidin-3- yl)propanoic acid) 40-a 3,3′-((((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)azanediyl)bis(methylene))bis (1H-benzo[d]imidazole-7,2-diyl))bis(2- (pyrrolidin-3-yl)propanoic acid) 41-a 3,3′-((((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)azanediyl)bis(methylene)) bis(naphthalene-8,2-diyl))bis(2-(pyrrolidin-3- yl)propanoic acid) 42-a 3,3′-((((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)azanediyl)bis(methylene))bis (quinoline-4,6-diyl))bis(2-(pyrrolidin-3- yl)propanoic acid) 43-a 3,3′-((((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)azanediyl)bis(methylene)) bis(quinoline-2,7-diyl))bis(2-(pyrrolidin-3- yl)propanoic acid) 44-a 3,3′-((((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)azanediyl)bis(methylene))bis (pyrrolo[3,4-b]pyrrole-4,3-diyl))bis(2- (pyrrolidin-3-yl)propanoic acid) 45-a 3,3′-((((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)azanediyl)bis(methylene)) bis(1-methyl-1H-benzo[d]imidazole-7,2- diyl))bis(2-(pyrrolidin-3-yl)propanoic acid) 46-a 3,3′-((((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)azanediyl)bis(methylene))bis (quinazoline-8,2-diyl))bis(2-(pyrrolidin-3- yl)propanoic acid) 47-a 3,3′,3″- ((nitrilotris(methylene))tris(benzofuran-3,5- diyl))tris(2-(pyrrolidin-3-yl)propanoic acid) 48-a 3,3′,3″-((nitrilotris(methylene))tris(benzofuran- 2,5-diyl))tris(2-(pyrrolidin-3-yl)propanoic acid) 49-a 3,3′,3″- ((nitrilotris(methylene))tris(benzo[b]thiophene- 3,5-diyl))tris(2-(pyrrolidin-3- yl)propanoic acid) 50-a 3,3′,3″-((nitrilotris(methylene))tris(1H-indole- 3,5-diyl))tris(2-(pyrrolidin-3-yl)propanoic acid) 51-a 3,3′,3″- ((nitrilotris(methylene))tris(benzofuran-7,2- diyl))tris(2-(pyrrolidin-3-yl)propanoic acid) 52-a 3,3′,3″-((nitrilotris(methylene))tris(1H- indazole-3,5-diyl))tris(2-(pyrrolidin-3- yl)propanoic acid) 53-a 3,3′,3″-((nitrilotris(methylene))tris(1H- benzo[d]imidazole-2,5-diyl))tris(2- (pyrrolidin-3-yl)propanoic acid) 54-a 3,3′,3″-((nitrilotris(methylene))tris(1H- pyrazolo[4,3-b]pyridine-3,5-diyl))tris(2- (pyrrolidin-3-yl)propanoic acid) 55-a 3,3′,3″- ((nitrilotris(methylene))tris(pyrrolo[3,4- b]pyrrole-4,3-diyl))tris(2-(pyrrolidin-3- yl)propanoic acid) 56-a 3,3′,3″-((nitrilotris(methylene))tris(1H- benzo[d]imidazole-7,2-diyl))tris(2-(pyrrolidin- 3-yl)propanoic acid) 57-a 3,3′,3″-((nitrilotris(methylene))tris(1-methyl- 1H-benzo[d]imidazole-7,2-diyl))tris(2- (pyrrolidin-3-yl)propanoic acid) 58-a 3,3′,3″- ((nitrilotris(methylene))tris(naphthalene-8,2- diyl))tris(2-(pyrrolidin-3-yl)propanoic acid) 59-a 3,3′,3″- ((nitrilotris(methylene))tris(quinoline-4,6- diyl))tris(2-(pyrrolidin-3-yl)propanoic acid) 60-a 3,3′,3″-((nitrilotris(methylene))tris(quinoline- 2,7-diyl))tris(2-(pyrrolidin-3-yl)propanoic acid) 61-a 3,3′,3″- ((nitrilotris(methylene))tris(quinazoline-8,2- diyl))tris(2-(pyrrolidin-3-yl)propanoic acid) 62-a 3,3′-((((3-fluoro-5- methoxybenzyl)azanediyl)bis(ethane-2,1- diyl))bis(1H-indole-1,6-diyl))bis(2-(pyrrolidin- 3-yl)propanoic acid) 63-a 3,3′-((((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)-5- fluorobenzyl)azanediyl)bis(ethane-2,1- diyl))bis(3,1-phenylene))bis(2-(pyrrolidin-3- yl)propanoic acid) 64-a 3,3′-((((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)azanediyl)bis(methylene))bis ([1,1′-biphenyl]-3′,3-diyl))bis(2-(pyrrolidin-3- yl)propanoic acid) 65-a 3,3′,3″-((nitrilotris(ethane-2,1- diyl))tris(benzene-3,1-diyl))tris(2- (pyrrolidin-3-yl)propanoic acid) 66-a 3,3′,3″-((nitrilotris(ethane-2,1-diyl))tris(5- fluorobenzene-3,1-diyl))tris(2-(pyrrolidin-3- yl)propanoic acid) 67-a 3,3′,3″-((nitrilotris(ethane-2,1- diyl))tris(benzofuran-3,5-diyl))tris(2- (pyrrolidin-3-yl)propanoic acid) 68-a 3,3′,3″-((nitrilotris(ethane-2,1-diyl))tris(1H- indole-1,6-diyl))tris(2-(pyrrolidin-3- yl)propanoic acid) 69-a 3,3′,3″-((nitrilotris(ethane-2,1- diyl))tris(isoquinoline-1,7-diyl))tris(2- (pyrrolidin-3-yl)propanoic acid) 70-a 3,3′-((((2-(6-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)-1H-indol-1- yl)ethyl)azanediyl)bis(ethane-2,1- diyl))bis(benzofuran-4,2-diyl))bis(2- (pyrrolidin-3-yl)propanoic acid) 71-a 3,3′-((((2-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenoxy)ethyl)azanediyl)bis(ethane- 2,1-diyl))bis(3,1-phenylene))bis(2- (pyrrolidin-3-yl)propanoic acid) 72-a 3,3′-((((2-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)-5- methoxyphenoxy)ethyl)azanediyl)bis(ethane- 2,1-diyl))bis(5-methoxy-3,1-phenylene))bis(2- (pyrrolidin-3-yl)propanoic acid) 73-a 3,3′,3″-((nitrilotris(methylene))tris([1,1′- biphenyl]-3′,3-diyl))tris(2-(pyrrolidin-3- yl)propanoic acid) 74-a 3,3′-(((((5-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)pyridin-3- yl)methyl)azanediyl)bis(methylene))bis([3,3′- bipyridine]-5′,5-diyl))bis(2-(pyrrolidin-3- yl)propanoic acid) 75-a 3,3′,3″-((nitrilotris(methylene))tris([3,3′- bipyridine]-5′,5-diyl))tris(2-(pyrrolidin-3- yl)propanoic acid) 76-a 4,4′-((((2-(3-carboxy-3-(pyrrolidin-3- yl)propyl)benzofuran-4- yl)methyl)azanediyl)bis(benzofuran-4,2- diyl))bis(2-(pyrrolidin-3-yl)butanoic acid) 77-a 4,4′,4″- ((nitrilotris(methylene))tris(benzofuran-4,2- diyl))tris(2-(pyrrolidin-3-yl)butanoic acid) 78-a 4,4′,4″-((nitrilotris(methylene))tris(1H- benzo[d]imidazole-4,2-diyl))tris(2-(pyrrolidin- 3-yl)butanoic acid) 79-a 3,3′-((((2-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenoxy)ethyl)azanediyl)bis(2- oxoethane-2,1-diyl))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid) 80-a 3,3′-((2,2′-((2-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenoxy)ethyl)azanediyl)bis(acetyl)) bis(3,1-phenylene))bis(2-(pyrrolidin-3- yl)propanoic acid) 81-a 3,3′-((((2-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenoxy)acetyl)azanediyl)bis(ethane- 2,1-diyl))bis(3,1-phenylene))bis(2- (pyrrolidin-3-yl)propanoic acid) 82-a 2,2′,2″- ((((nitrilotris(methylene))tris(benzofuran-4,2- diyl))tris(methylene))tris(oxy))tris(2- (pyrrolidin-3-yl)acetic acid) 85-a 3,3′,3″-(((oxo-15- phosphanetriyl)tris(methylene))tris(benzene- 3,1-diyl))tris(2-(pyrrolidin-3-yl)propanoic acid) 86-a 3-[3-(3-{3-[2-carboxy-2-(tetrahydro-1H-pyrrol- 3-yl)ethyl]phenyl}-2-({3-[2-carboxy-2- (tetrahydro-1H-pyrrol-3- yl)ethyl]phenyl}methyl)-2- hydroxypropyl)phenyl]-2-(tetrahydro-1H- pyrrol-3-yl)propanoic acid 87-a 3-[3-(3-{3-[2-carboxy-2-(tetrahydro-1H- pyrrol-3-yl)ethyl]phenyl}-2-({3-[2-carboxy- 2-(tetrahydro-1H-pyrrol-3- yl)ethyl]phenyl}methyl)-2- methoxypropyl)phenyl]-2-(tetrahydro-1H- pyrrol-3-yl)propanoic acid 88-a 3-[3-(3-{3-[2-carboxy-2-(tetrahydro-1H-pyrrol- 3-yl)ethyl]phenyl}-2-({3-[2-carboxy-2- (tetrahydro-1H-pyrrol-3- yl)ethyl]phenyl}methyl)prop-2-enyl)phenyl]-2- (tetrahydro-1H-pyrrol-3-yl)propanoic acid 89-a 3,3′-((((3-fluoro-5- methoxyphenethyl)azanediyl)bis(methylene)) bis(3,1-phenylene))bis(2-(pyrrolidin-3- yl)propanoic acid) 90-a 3,3′,3″-((nitrilotris(methylene-d2))tris(benzene- 3,1-diyl))tris(2-(pyrrolidin-3-yl)propanoic acid) 91-a 3,3′,3″-((nitrilotris(methylene))tris(benzene- 3,1-diyl))tris(2-(pyrrolidin-3-yl)propanoic- 3,3-d2 acid) 92-a 3,3′,3″-((nitrilotris(methylene))tris(benzene- 3,1-diyl))tris(2-(pyrrolidin-3-yl-5,5- d2)propanoic acid) 93-a 3,3′-((((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)azanediyl)bis(methylene- d2))bis(3,1-phenylene))bis(2-(pyrrolidin-3- yl)propanoic acid) 94-a 3,3′-(((((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenyl)methyl- d2)azanediyl)bis(methylene))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid) 95-a 3,3′-((((2-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenoxy)acetyl)azanediyl)bis (methylene))bis(3,1-phenylene))bis(2-(pyrrolidin- 3-yl)propanoic acid) 96-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)(2-(3-(2-carboxy-2-(pyrrolidin- 3-yl)ethyl)phenoxy)ethyl)amino)-2- oxoethyl)phenyl)-2-(pyrrolidin-3-yl)propanoic acid 97-a 3-(3-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)-N-(2-(3-(2-carboxy-2-(pyrrolidin- 3-yl)ethyl)phenoxy)ethyl)benzamido)methyl) phenyl)-2-(pyrrolidin-3-yl)propanoic acid 98-a 3,3′-((((3-(2-carboxy-2-(pyrrolidin-3-yl)ethyl- 1,1-d2)benzyl)azanediyl)bis(methylene))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid) 99-a 3-(3-(2-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)-N-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)benzamido)ethyl)phenyl)-2- (pyrrolidin-3-yl)propanoic acid100-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenethyl)(2-(3-(2-carboxy-2- (pyrrolidin-3-yl)ethyl)phenoxy)ethyl)amino)-2- oxoethyl)phenyl)-2-(pyrrolidin-3-yl)propanoic acid101-a 3,3′,3″- ((nitrilotris(methylene))tris(benzo[b]thiophene- 4,2-diyl))tris(2-(pyrrolidin-3- yl)propanoic acid)102-a 3,3′,3″-((nitrilotris(methylene))tris(benzofuran- 7,5-diyl))tris(2-(pyrrolidin-3-yl)propanoic acid)103-a 3,3′,3″- ((nitrilotris(methylene))tris(benzo[b]thiophene- 6,2-diyl))tris(2-(pyrrolidin-3- yl)propanoic acid)104-a 3,3′,3″- ((nitrilotris(methylene))tris(benzo[b]thiophene- 5,2-diyl))tris(2-(pyrrolidin-3-yl)propanoic acid)105-a 3,3′-((((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)azanediyl)bis(methylene)) bis(3,1-phenylene))bis(2-(pyrrolidin-3- yl)propanoic-3,3-d2 acid)106-a 3-(3-(2-(3-(2-carboxy-2-(pyrrolidin-3-yl)ethyl)- N-(2-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenoxy)ethyl)benzamido)ethyl)phenyl)- 2-(pyrrolidin-3-yl)propanoic acid107-a 3,3′-((((2-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenyl)acetyl)azanediyl)bis(ethane- 2,1-diyl))bis(3,1-phenylene))bis(2- (pyrrolidin-3-yl)propanoic acid)108-a 3,3′-((((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzoyl)azanediyl)bis(ethane-2,1- diyl))bis(3,1-phenylene))bis(2-(pyrrolidin-3- yl)propanoic acid)109-a 3,3′,3″- ((nitrilotris(methylene))tris(benzofuran-3,6- diyl))tris(2-(pyrrolidin-3-yl)propanoic acid)110-a 3,3′,3″-((nitrilotris(methylene))tris(benzofuran- 2,4-diyl))tris(2-(pyrrolidin-3-yl)propanoic acid)111-a 3,3′-(((((2-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenyl)acetyl)azanediyl)bis(ethane- 2,1-diyl))bis(oxy))bis(3,1-phenylene))bis(2- (pyrrolidin-3-yl)propanoic acid)112-a 3,3′-(((((2-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenyl)-2- oxoethyl)azanediyl)bis(ethane-2,1- diyl))bis(oxy))bis(3,1-phenylene))bis(2- (pyrrolidin-3-yl)propanoic acid)113-a 3,3′-(((((2-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenoxy)acetyl)azanediyl)bis(ethane- 2,1-diyl))bis(oxy))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid)114-a 3,3′-(((((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenyl)glycyl)azanediyl)bis(methylene)) bis(3,1-phenylene))bis(2-(pyrrolidin-3- yl)propanoic acid)115-a 3,3′-((((2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenyl)thio)acetyl)azanediyl)bis (methylene))bis(3,1-phenylene))bis(2- (pyrrolidin-3-yl)propanoic acid)116-a 3,3′-((((3-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenoxy)-2- oxopropyl)azanediyl)bis(methylene))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid)117-a 3,3′-((piperazine-1,4- diylbis(methylene))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid)118-a 3,3′,3″-((nitrilotris(methylene))tris(thiophene- 5,2-diyl))tris(2-(pyrrolidin-3-yl)propanoic acid)119-a 3,3′-(((((4-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)furan-2- yl)methyl)azanediyl)bis(methylene))bis(furan- 4,2-diyl))bis(2-(pyrrolidin-3-yl)propanoic acid)120-a 3,3′,3″-((nitrilotris(methylene))tris(oxazole-2,4- diyl))tris(2-(pyrrolidin-3-yl)propanoic acid)121-a 3,3′,3″-((nitrilotris(methylene))tris(thiazole- 5,2-diyl))tris(2-(pyrrolidin-3-yl)propanoic acid)122-a 3,3′,3″-(((benzene-1,3,5- triyltris(oxy))tris(methylene))tris(benzene-3,1- diyl))tris(2-(pyrrolidin-3-yl)propanoic acid)123-a triethyl 3,3′,3″- ((nitrilotris(methylene))tris(benzene-3,1- diyl))tris(2-(pyrrolidin-3-yl)propanoate-3′,3′-d2)124-a tris((isobutyryloxy)methyl) 3,3′,3″- ((nitrilotris(methylene))tris(benzene-3,1- diyl))tris(2-(pyrrolidin-3-yl)propanoate-3′,3′-d2)126-a 3,3′-(((((2-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzofuran-5- yl)methyl)azanediyl)bis(methylene))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid)127-a 3,3′,3″-((nitrilotris(methylene))tris(benzofuran- 5,2-diyl))tris(2-(pyrrolidin-3-yl)propanoic acid)128-a 3,3′,3″- ((nitrilotris(methylene))tris(benzo[b]thiophene- 5,3-diyl))tris(2-(pyrrolidin-3- yl)propanoic acid)129-a 3-(3-(2-(1,3-bis(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenethyl)ureido)ethoxy)phenyl)-2- (pyrrolidin-3-yl)propanoic acid130-a 3,3′-((((2-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenyl)-2- oxoethyl)azanediyl)bis(methylene))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid)131-a 3-(3-(3-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)-3-(2-(3-(2-carboxy-2- (pyrrolidin-3- yl)ethyl)phenoxy)ethyl)ureido)phenyl)-2- (pyrrolidin-3-yl)propanoic acid132-a 3,3′-(((2-(((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)oxy)methyl)piperazine-1,4- diyl)bis(methylene))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid)133-a 3,3′,3″-((nitrilotris(methylene))tris(1-methyl- 1H-benzo[d]imidazole-6,2-diyl))tris(2- (pyrrolidin-3-yl)propanoic acid)134-a 3-(3-((2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)(2-(3-(2-carboxy-2- (pyrrolidin-3- yl)ethyl)phenoxy)ethyl)amino)-2- oxoethyl)amino)phenyl)-2-(pyrrolidin-3- yl)propanoic acid135-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)(2-(3-(2-carboxy-2-(pyrrolidin- 3-yl)ethyl)phenoxy)ethyl)amino)-2- oxoethoxy)phenyl)-2-(pyrrolidin-3- yl)propanoic acid136-a 3,3′,3″-((nitrilotris(methylene))tris(1H- indazole-3,6-diyl))tris(2-(pyrrolidin-3- yl)propanoic acid)137-a 3,3′,3″-((nitrilotris(methylene))tris(thiophene- 5,3-diyl))tris(2-(pyrrolidin-3-yl)propanoic acid)138-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)(((3-(2-carboxy-2- (pyrrolidin-3- yl)ethyl)phenyl)thio)carbonyl)amino)ethoxy) phenyl)-2-(pyrrolidin-3-yl)propanoic acid139-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenoxy)carbonyl)amino)ethoxy)phenyl)- 2-(pyrrolidin-3-yl)propanoic acid140-a 3-(3-(3-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)(2-(3-(2-carboxy-2- (pyrrolidin-3- yl)ethyl)phenoxy)ethyl)amino)-3- oxopropyl)phenyl)-2-(pyrrolidin-3- yl)propanoic acid141-a 3-(3-(2-(1,3-bis(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)ureido)ethoxy)phenyl)-2- (pyrrolidin-3-yl)propanoic acid142-a 3-(3-(2-((2-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenoxy)ethyl)amino)-2- oxoethyl)phenyl)-2-(pyrrolidin-3- yl)propanoic acid143-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)amino)-2-oxoethyl)phenyl)-2- (pyrrolidin-3-yl)propanoic acid144-a 3,3′,3″- ((nitrilotris(methylene))tris(benzo[d]isoxazole- 6,3-diyl))tris(2-(pyrrolidin-3-yl)propanoic acid)145 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)(((3-(2-carboxy-2-(pyrrolidin- 3-yl)ethyl)benzyl)oxy)carbonyl)amino)ethoxy) phenyl)-2-(pyrrolidin-3-yl)propanoic acid146-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)(2-((3-(2-carboxy-2- (pyrrolidin-3- yl)ethyl)phenyl)amino)ethyl)amino)-2- oxoethyl)phenyl)-2-(pyrrolidin-3- yl)propanoic acid147-a 3-(3-(3-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)(2-((3-(2-carboxy-2- (pyrrolidin-3- yl)ethyl)phenyl)amino)ethyl)amino)-3- oxopropyl)phenyl)-2-(pyrrolidin-3- yl)propanoic acid148-a 3,3′-(((((3-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenyl)propanoyl)azanediyl)bis (ethane-2,1-diyl))bis(oxy))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid)149-a 3,3′,3″-(((benzene-1,3,5- triyltris(methylene))tris(oxy))tris(benzene-3,1- diyl))tris(2-(pyrrolidin-3-yl)propanoic acid)150-a 3,3′-(((2-(((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)oxy)methyl)piperazine-1,4- diyl)bis(methylene))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid)152-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)-5-fluorobenzyl)(2-(3-(2-carboxy-2- (pyrrolidin-3-yl)ethyl)-5- fluorophenoxy)ethyl)amino)-2-oxoethyl)-5- fluorophenyl)-2-(pyrrolidin-3-yl)propanoic acid153-a 3-(5-(2-(2-(5-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)pyridin-3-yl)-N-((5-(2-carboxy-2- (pyrrolidin-3-yl)ethyl)pyridin-3- yl)methyl)acetamido)ethoxy)pyridin-3-yl)- 2-(pyrrolidin-3-yl)propanoic acid154-a 3,3′,3″,3″′-(((1,4,7,10-tetraazacyclododecane-1,4,7,10- tetrayl)tetrakis(methylene))tetrakis(benzene- 3,1-diyl))tetrakis(2-(pyrrolidin-3-yl)propanoic acid)155-a 3,3′,3″-(((1,5,9-triazacyclododecane-1,5,9- triyl)tris(methylene))tris(benzene-3,1- diyl))tris(2-(pyrrolidin-3-yl)propanoic acid)156-a 3,3′,3″-(((benzene-1,3,5- triyltris(azanediyl))tris(methylene))tris(benzene- 3,1-diyl))tris(2-(pyrrolidin-3-yl)propanoic acid)157-a 3,3′,3″-(((benzene-1,3,5- triyltris(oxy))tris(ethane-2,1- diyl))tris(benzene-3,1-diyl))tris(2- (pyrrolidin-3-yl)propanoic acid)158-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)(2-((3-(2-carboxy-2- (pyrrolidin-3- yl)ethyl)phenyl)thio)ethyl)amino)-2- oxoethyl)phenyl)-2-(pyrrolidin-3-yl)propanoic acid159-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)(3-(3-(2-carboxy-2- (pyrrolidin-3- yl)ethyl)phenoxy)propyl)amino)-2- oxoethyl)phenyl)-2-(pyrrolidin-3- yl)propanoic acid160-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)(2-((3-(2-carboxy-2- (pyrrolidin-3- yl)ethyl)benzyl)oxy)ethyl)amino)-2- oxoethyl)phenyl)-2-(pyrrolidin-3-yl)propanoic acid161-a 3-(3-(2-((2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)oxy)ethyl)(3-(2-carboxy-2- (pyrrolidin-3-yl)ethyl)phenethyl)amino)-2- oxoethyl)phenyl)-2-(pyrrolidin-3- yl)propanoic acid162-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenethyl)((3-(2-carboxy-2- (pyrrolidin-3- yl)ethyl)phenoxy)carbonyl)amino)ethoxy) phenyl)-2-(pyrrolidin-3-yl)propanoic acid163-a 3,3′-((((((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenoxy)carbonyl)azanediyl)bis (ethane-2,1-diyl))bis(oxy))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid)164-a 3-(3-(2-((((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)oxy)carbonyl)(2-((3-(2- carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)oxy)ethyl)amino)ethyl)phenyl)- 2-(pyrrolidin-3-yl)propanoic acid165-a 3,3′-((((((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenyl)carbamoyl)azanediyl)bis (ethane-2,1-diyl))bis(oxy))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid)166-a 3-(3-(2-(3-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)-1-(2-(3-(2-carboxy-2- (pyrrolidin-3- yl)ethyl)phenoxy)ethyl)ureido)ethyl)phenyl)-2- (pyrrolidin-3-yl)propanoic acid167-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)(2-(3-(2-carboxy-2- (pyrrolidin-3- yl)ethyl)phenoxy)ethyl)amino)ethyl)phenyl)- 2-(pyrrolidin-3-yl)propanoic acid168-a 3-(4-(2-((4-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)(2-(4-(2-carboxy-2-(pyrrolidin- 3-yl)ethyl)phenoxy)ethyl)amino)-2- oxoethyl)phenyl)-2-(pyrrolidin-3-yl)propanoic acid169-a 3-(3-{[(2-{5-[2-carboxy-2-(tetrahydro-1H- pyrrol-3-yl)ethyl]-3- deuteriophenyl}acetyl)[2-({3-[2-carboxy-2- (tetrahydro-1H-pyrrol-3-yl)ethyl]-5- deuteriophenyl}oxy)ethyl]amino]methyl}-5- deuteriophenyl)-2-(tetrahydro-1H-pyrrol-3- yl)propanoic acid170-a 3,3′-((((2-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)-5- chlorophenyl)acetyl)azanediyl)bis(ethane-2,1- diyl))bis(5-chloro-3,1-phenylene))bis(2- (pyrrolidin-3-yl)propanoic acid)171-a 3-(3-(3-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)-5-methylbenzyl)-3-(2-(3-(2- carboxy-2-(pyrrolidin-3-yl)ethyl)-5- methylphenoxy)ethyl)ureido)-5- methylphenyl)-2-(pyrrolidin-3-yl)propanoic acid172-a 3-(3-(2-((3-(2-carboxy-2-fluoro-2-(pyrrolidin- 3-yl)ethyl)benzyl)(2-(3-(2-carboxy-2-fluoro-2- (pyrrolidin-3-yl)ethyl)phenoxy)ethyl)amino)-2- oxoethyl)phenyl)-2-fluoro-2-(pyrrolidin-3- yl)propanoic acid173-a 3-[3-({2-[(2-{3-[2-carboxy-2-(tetrahydro- 1H-pyrrol-3-yl)ethyl]phenyl}acetyl)({3-[2- carboxy-2-(tetrahydro-1H-pyrrol-3- yl)ethyl]phenyl}methyl)amino]-2,2- dideuterioethyl}oxy)phenyl]-2-(tetrahydro- 1H-pyrrol-3-yl)propanoic acid174-a 3,3′-(((((2-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)-5- methylphenyl)acetyl)azanediyl)bis(ethane-2,1- diyl))bis(oxy))bis(5-methyl-3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid)175-a 3-(6-(2-(2-(6-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)pyrimidin-4-yl)-N-((6-(2-carboxy- 2-(pyrrolidin-3-yl)ethyl)pyrimidin-4- yl)methyl)acetamido)ethoxy)pyrimidin-4- yl)-2-(pyrrolidin-3-yl)propanoic acid176-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)-5-methoxybenzyl)(2-(3-(2-carboxy-2- (pyrrolidin-3-yl)ethyl)-5- methoxyphenoxy)ethyl)amino)-2-oxoethyl)-5- methoxyphenyl)-2-(pyrrolidin-3-yl)propanoic acid177-a 3-(3-(2-((2-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenoxy)ethyl)((4-(2-carboxy-2- (pyrrolidin-3-yl)ethyl)thiophen-2- yl)methyl)amino)-2-oxoethyl)phenyl)-2- (pyrrolidin-3-yl)propanoic acid178-a 3-(5-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)(2-(3-(2-carboxy-2-(pyrrolidin- 3-yl)ethyl)phenoxy)ethyl)amino)-2- oxoethyl)thiophen-3-yl)-2-(pyrrolidin-3- yl)propanoic acid179-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)(2-((5-(2-carboxy-2- (pyrrolidin-3-yl)ethyl)thiophen-3- yl)oxy)ethyl)amino)-2-oxoethyl)phenyl)-2- (pyrrolidin-3-yl)propanoic acid180-a 3-(5-(2-((2-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenoxy)ethyl)((4-(2-carboxy-2- (pyrrolidin-3-yl)ethyl)thiophen-2- yl)methyl)amino)-2-oxoethyl)thiophen-3-yl)-2- (pyrrolidin-3-yl)propanoic acid181-a 3-(5-((2-(2-(4-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)thiophen-2-yl)-N-((4-(2-carboxy-2- (pyrrolidin-3-yl)ethyl)thiophen-2- yl)methyl)acetamido)ethoxy)methyl)thiophen- 3-yl)-2-(pyrrolidin-3-yl)propanoic acid182-a 3-(3-(2-((2-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenoxy)ethyl)((5-(2-carboxy-2- (pyrrolidin-3-yl)ethyl)thiophen-3- yl)methyl)amino)-2-oxoethyl)phenyl)-2- (pyrrolidin-3-yl)propanoic acid183-a 3-(4-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)(2-(3-(2-carboxy-2- (pyrrolidin-3- yl)ethyl)phenoxy)ethyl)amino)-2- oxoethyl)thiophen-2-yl)-2-(pyrrolidin-3- yl)propanoic acid184-a 3-(4-(2-((2-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenoxy)ethyl)((5-(2-carboxy-2- (pyrrolidin-3-yl)ethyl)thiophen-3- yl)methyl)amino)-2-oxoethyl)thiophen-2-yl)-2- (pyrrolidin-3-yl)propanoic acid185-a 3-(4-((2-(2-(5-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)thiophen-3-yl)-N-((5-(2-carboxy-2- (pyrrolidin-3-yl)ethyl)thiophen-3- yl)methyl)acetamido)ethoxy)methyl)thiophen- 2-yl)-2-(pyrrolidin-3-yl)propanoic acid186-a 3,3′-(((((2-(4-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)furan-2-yl)acetyl)azanediyl)bis(ethane- 2,1-diyl))bis(oxy))bis(3,1-phenylene))bis(2- (pyrrolidin-3-yl)propanoic acid)187-a 3-(3-(2-((2-((5-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)furan-3-yl)oxy)ethyl)(2-(3-(2- carboxy-2-(pyrrolidin-3- yl)ethyl)phenoxy)ethyl)amino)-2- oxoethyl)phenyl)-2-(pyrrolidin-3- yl)propanoic acid188-a 3,3′-(((((2-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenyl)acetyl)azanediyl)bis(ethane- 2,1-diyl))bis(oxy))bis(furan-4,2-diyl))bis(2- (pyrrolidin-3-yl)propanoic acid)189-a 3,3′-(((((2-(5-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)furan-3- yl)acetyl)azanediyl)bis(ethane-2,1- diyl))bis(oxy))bis(furan-4,2-diyl))bis(2- (pyrrolidin-3-yl)propanoic acid)190-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3-yl)ethyl- 1,1-d2)benzyl)(2-(3-(2-carboxy-2-(pyrrolidin- 3-yl)ethyl-1,1-d2)phenoxy)ethyl)amino)-2- oxoethyl)phenyl)-2-(pyrrolidin-3-yl)propanoic- 3,3-d2 acid191-a 3,3′-(((((2-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl-1,1- d2)phenyl)acetyl)azanediyl)bis(ethane-2,1- diyl))bis(oxy))bis(3,1-phenylene))bis(2- (pyrrolidin-3-yl)propanoic-3,3-d2 acid)192-a 3-(3-(2-(((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenoxy)carbonyl)((3-(2-carboxy-2- (pyrrolidin-3-yl)ethyl)phenyl)methyl- d2)amino)ethoxy)phenyl)-2-(pyrrolidin-3- yl)propanoic acid193-a 3-(3-(2-((2-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenoxy)ethyl)((3-(2-carboxy-2- (pyrrolidin-3-yl)ethyl)phenyl)methyl- d2)amino)-2-oxoethyl)phenyl)-2- (pyrrolidin-3-yl)propanoic acid194-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3-yl)ethyl- 2-d)benzyl)(2-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl-2-d)phenoxy)ethyl)amino)-2- oxoethyl)phenyl)-2-(pyrrolidin-3-yl)propanoic-2-d acid195-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3-yl- 5,5-d2)ethyl)benzyl)(2-(3-(2-carboxy-2- (pyrrolidin-3-yl-5,5- d2)ethyl)phenoxy)ethyl)amino)-2- oxoethyl)phenyl)-2-(pyrrolidin-3-yl-5,5- d2)propanoic acid196-a 3-(3-(2-((2-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)-5-fluorophenoxy)ethyl)((3-(2- carboxy-2-(pyrrolidin-3-yl)ethyl)-5- fluorophenyl)methyl-d2)amino)-2-thioxoethyl)- 5-fluorophenyl)-2-(pyrrolidin-3-yl)propanoic acid197-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)(2-(3-(2-carboxy-2- (pyrrolidin-3- yl)ethyl)phenoxy)ethyl)amino)-2- thioxoethyl)phenyl)-2-(pyrrolidin-3- yl)propanoic acid198-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)(2-((3-(2-carboxy-2- (pyrrolidin-3- yl)ethyl)phenyl)thio)ethyl)amino)-2- thioxoethyl)phenyl)-2-(pyrrolidin-3- yl)propanoic acid199-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)-5-chlorobenzyl)(2-(3-(2-carboxy- 2-(pyrrolidin-3-yl)ethyl)-5- chlorophenoxy)ethyl)amino)-2-thioxoethyl)- 5-chlorophenyl)-2-(pyrrolidin-3- yl)propanoic acid200-a 3-(3-((3-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)(2-(3-(2-carboxy-2-(pyrrolidin- 3-yl)ethyl)phenoxy)ethyl)amino)oxetan-3- yl)methyl)phenyl)-2-(pyrrolidin-3-yl)propanoic acid201-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)(1-(3-(2-carboxy-2- (pyrrolidin-3-yl)ethyl)phenyl)-2- methylpropan-2-yl)amino)ethoxy)phenyl)-2- (pyrrolidin-3-yl)propanoic acid202-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)(2-(3-(2-carboxy-2-(pyrrolidin- 3-yl)ethyl)phenoxy)ethyl)amino)-2,2- difluoroethyl)phenyl)-2-(pyrrolidin-3- yl)propanoic acid203-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)(2-(3-(2-carboxy-2- (pyrrolidin-3- yl)ethyl)phenoxy)ethyl)amino)-3,3,3- trifluoropropyl)phenyl)-2-(pyrrolidin-3- yl)propanoic acid204-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)-5-methylbenzyl)(2-(3-(2-carboxy-2- (pyrrolidin-3-yl)ethyl)-5- methylphenoxy)ethyl)amino)-2-oxoethyl)-5- methylphenyl)-2-(pyrrolidin-3-yl)propanoic acid205-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)-5-cyanobenzyl)(2-(3-(2-carboxy-2- (pyrrolidin-3-yl)ethyl)-5- cyanophenoxy)ethyl)amino)-2-oxoethyl)-5- cyanophenyl)-2-(pyrrolidin-3-yl)propanoic acid206-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)-5-hydroxybenzyl)(2-(3-(2-carboxy-2- (pyrrolidin-3-yl)ethyl)-5- hydroxyphenoxy)ethyl)amino)-2-oxoethyl)-5- hydroxyphenyl)-2-(pyrrolidin-3-yl)propanoic acid207-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)-5-(methylamino)benzyl)(2-(3-(2- carboxy-2-(pyrrolidin-3-yl)ethyl)-5- (methylamino)phenoxy)ethyl)amino)-2- oxoethyl)-5-(methylamino)phenyl)-2- (pyrrolidin-3-yl)propanoic acid208-a 3-(3-acetyl-5-((N-(2-(3-acetyl-5-(2-carboxy-2- (pyrrolidin-3-yl)ethyl)phenoxy)ethyl)-2-(3- acetyl-5-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenyl)acetamido)methyl)phenyl)-2- (pyrrolidin-3-yl)propanoic acid212-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)propyl)benzyl)(2-(3-(2-carboxy-2- (pyrrolidin-3- yl)propyl)phenoxy)ethyl)amino)-2- oxoethyl)phenyl)-2-methyl-2-(pyrrolidin-3- yl)propanoic acid213-a 2-(3-(2-((3-(2-carboxy-3,3,3-trifluoro-2- (pyrrolidin-3-yl)propyl)benzyl)(2-(3-(2- carboxy-3,3,3-trifluoro-2-(pyrrolidin-3- yl)propyl)phenoxy)ethyl)amino)-2- oxoethyl)benzyl)-3,3,3-trifluoro-2-(pyrrolidin- 3-yl)propanoic acid214-a 2-(3-(2-((3-(carboxy(pyrrolidin-3- yl)methoxy)benzyl)(2-(3- (carboxy(pyrrolidin-3- yl)methoxy)phenoxy)ethyl)amino)-2- oxoethyl)phenoxy)-2-(pyrrolidin-3-yl)acetic acid215-a 2-((3-(2-((2-(3-(carboxy(pyrrolidin-3- yl)methoxy)phenoxy)ethyl)(3- ((carboxy(pyrrolidin-3- yl)methyl)thio)benzyl)amino)-2- oxoethyl)phenyl)thio)-2-(pyrrolidin-3-yl)acetic acid216-a 2-((3-(2-((3-((carboxy(pyrrolidin-3- yl)methyl)amino)benzyl)(2-(3- ((carboxy(pyrrolidin-3- yl)methyl)amino)phenoxy)ethyl)amino)-2- oxoethyl)phenyl)amino)-2-(pyrrolidin-3- yl)acetic acid217-a 3-(3-(2-((3-(2-carboxy-2-(piperidin-4- yl)ethyl)benzyl)(2-(3-(2-carboxy-2-(piperidin- 4-yl)ethyl)phenoxy)ethyl)amino)-2- oxoethyl)phenyl)-2-(piperidin-4-yl)propanoic acid218-a 3-(3-(2-((3-(2-carboxy-2-(piperidin-3- yl)ethyl)benzyl)(2-(3-(2-carboxy-2- (piperidin-3-yl)ethyl)phenoxy)ethyl)amino)- 2-oxoethyl)phenyl)-2-(piperidin-3- yl)propanoic acid219-a 2-(azetidin-3-yl)-3-(3-(2-((3-(2-(azetidin-3-yl)- 2-carboxyethyl)benzyl)(2-(3-(2-(azetidin-3-yl)- 2-carboxyethyl)phenoxy)ethyl)amino)-2- oxoethyl)phenyl)propanoic acid220-a 2-(azepan-4-yl)-3-(3-(2-((3-(2-(azepan-4- yl)-2-carboxyethyl)benzyl)(2-(3-(2-(azepan- 4-yl)-2-carboxyethyl)phenoxy)ethyl)amino)- 2-oxoethyl)phenyl)propanoic acid221-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)(2-((3-(2-carboxy-2- (pyrrolidin-3- yl)ethyl)phenyl)selanyl)ethyl)amino)-2- oxoethyl)phenyl)-2-(pyrrolidin-3-yl)propanoic acid222-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)benzyl)(3-((3-(2-carboxy-2- (pyrrolidin-3- yl)ethyl)benzyl)oxy)propyl)amino)-2- oxoethyl)phenyl)-2-(pyrrolidin-3- yl)propanoic acid223-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenethyl)(2-((3-(2-carboxy-2- (pyrrolidin-3- yl)ethyl)phenyl)thio)ethyl)amino)-2- oxoethyl)phenyl)-2-(pyrrolidin-3-yl)propanoic acid224-a 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenethyl)(2-((3-(2-carboxy-2- (pyrrolidin-3- yl)ethyl)phenyl)amino)ethyl)amino)-2- oxoethyl)phenyl)-2-(pyrrolidin-3- yl)propanoic acid225-a 3-(3-(2-((2-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenoxy)ethyl)(2-((3-(2-carboxy-2- (pyrrolidin-3- yl)ethyl)phenyl)amino)ethyl)amino)-2- oxoethyl)phenyl)-2-(pyrrolidin-3-yl)propanoic acid226-a 3,3′-(((((2-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenyl)acetyl)azanediyl)bis(ethane- 2,1-diyl))bis(azanediyl))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid)227-a 3,3′-(((((2-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenyl)acetyl)azanediyl)bis(ethane- 2,1-diyl))bis(sulfanediyl))bis(3,1- phenylene))bis(2-(pyrrolidin-3-yl)propanoic acid)228-a 3-(3-(2-((2-(3-(2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenoxy)ethyl)(3-(3-(2-carboxy-2- (pyrrolidin-3- yl)ethyl)phenoxy)propyl)amino)-2- oxoethyl)phenyl)-2-(pyrrolidin-3- yl)propanoic acid 96-b (S)-3-(3-(2-((3-((S)-2-carboxy-2- (pyrrolidin-3-yl)ethyl)benzyl)(2-(3-((S)- 2-carboxy-2-(pyrrolidin-3- yl)ethyl)phenoxy)ethyl)amino)-2- oxoethyl)phenyl)-2-(pyrrolidin-3- yl)propanoic acid

[0416] In one embodiment of the invention, the compounds of the invention or a pharmaceutically acceptable salt thereof are selected from:Comp.No.Structure123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960616263646566676869707172737475767778798081828384858687888990919293949596979899100101102103104105106107108109110111112113114115116117118119120121122123124125126127128129130131132133134135136137138139140141142143144145146147148149150151152153154155156157158159160161162163164165166167168169170171172173174175176177178179180181182183184185186187188189190191192193194195196197198199200201202203204205206207208209210211212213214215216217218219220221222223224225226227228

[0417] In one embodiment of the invention, the compound is 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3-yl)ethyl)benzyl)(2-(3-(2-carboxy-2-(pyrrolidin-3-yl)ethyl)phenoxy)ethyl)amino)-2-oxoethyl)phenyl)-2-(pyrrolidin-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof:

[0418] In one embodiment of the invention, the compound is 3-(3-(2-((3-(2-carboxy-2-(pyrrolidin-3-yl)ethyl)benzyl)(2-(3-(2-carboxy-2-(pyrrolidin-3-yl)ethyl)phenoxy)ethyl)amino)-2-oxoethyl)phenyl)-2-(pyrrolidin-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof, in a stereoisomeric form:

[0419] In one embodiment of the invention, the compounds is(S)-3-(3-(2-((3-((S)-2-carboxy-2-(pyrrolidin-3-yl)ethyl)benzyl)(2-(3-((S)-2-carboxy-2-(pyrrolidin-3-yl)ethyl)phenoxy)ethyl)amino)-2-oxoethyl)phenyl)-2-(pyrrolidin-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof:

[0420] In one embodiment of the invention, the compounds is(S)-3-(3-(2-((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)(2-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenoxy)ethyl)amino)-2-oxoethyl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid, or a pharmaceutically acceptable salt thereof:

[0421] In one embodiment of the invention, the compounds is(S)-3-(3-(2-((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)(2-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenoxy)ethyl)amino)-2-oxoethyl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid, or a deuterated derivative form thereof, or a pharmaceutically acceptable salt thereof:

[0422] In one embodiment of the invention, the compounds is (2S,2'S)-3,3′-(((((2-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)acetyl)azanediyl)bis(ethane-2,1-diyl))bis(oxy))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid), or a deuterated derivative form thereof, or a pharmaceutically acceptable salt thereof:

[0423] In one embodiment of the invention, the compounds is(S)-3-(3-(2-((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl) ((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenoxy)carbonyl)amino)ethoxy)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid, or a deuterated derivative form thereof, or a pharmaceutically acceptable salt thereof:

[0424] In one embodiment of the invention, the compounds of the invention or a pharmaceutically acceptable salt thereof are selected from:wherein * represents the connecting end with N;CompoundNo.Z31′Z11′Z21′229C(O)CH2CH2CH2CH2230C(O)CH2*CH2CH2S231C(O)CH2*CH2CH2NH232C(O)CH2*CH2CH2CH2O233C(O)CH2*CH2CH2C(O)234C(O)CH2*CH2CH2C(S)235C(O)CH2*CH2CH2C(O)O236C(O)CH2*CH2CH2C(O)NH237C(O)CH2*CH2CH2C(O)NCH2238C(O)CH2*CH2CH2NHC(O)239C(O)CH2CH2CH2CH2CH2240C(O)CH2CH2*CH2CH2S241C(O)CH2CH2*CH2CH2CH2O242C(O)*CH2CH2O*CH2CH2O243C(O)*CH2CH2O*CH2CH2S244C(O)*CH2CH2O*CH2CH2NH245C(O)*CH2CH2O*CH2CH2C(O)246C(O)*CH2CH2O*CH2CH2C(O)NH247*C(O)CH2CH2CH2248*C(O)CH2CH2CH2CH2249*C(O)CH2CH2CH2CH2CH2CH2250*C(O)CH2*CH2CH2OCH2CH2CH2251*C(O)CH2*CH2CH2O*CH2CH2S252*C(O)CH2CH2*CH2CH2O*CH2CH2CH2S253*C(O)CH2CH2*CH2CH2O*CH2CH2C(O)254*C(O)CH2CH2*CH2CH2OCH2CH2255*C(O)CH2CH2CH2*CH2CH2CH2O256*C(O)CH2CH2CH2*CH2CH2C(O)257*C(O)CH2CH2CH2*CH2CH2C(O)O258*C(O)CH2CH2CH2*CH2CH2C(O)NH259*CH2C(O)CH2CH2CH2260*CH2C(O)CH2*CH2CH2O261*CH2C(O)CH2*CH2CH2NH262*CH2CH2C(O)CH2CH2263*CH2CH2C(O)CH2CH2CH2264*CH2CH2C(O)CH2*CH2CH2O265*CH2CH2C(O)CH2*CH2CH2S266*CH2CH2O*CH2CH2O*CH2CH2O267*CH2CH2O*CH2CH2O*CH2CH2C(O)268*CH2CH2O*CH2CH2O*CH2CH2C(O)NH269*CH2CH2NHCH2*CH2CH2C(O)NCH2270*CH2CH2NHCH2*CH2CH2NHC(O)271*CH2CH2NH*CH2CH2NH*CH2CH2O272*CH2CH2NH*CH2CH2NCH2*CH2CH2C(O)273*CH2CH2NH*CH2CH2O*CH2CH2C(O)NH274*C(O)OCH2CH2*CH2CH2NH275*C(O)OCH2CH2*CH2CH2S276*C(O)OCH2CH2CH2*CH2CH2O277*C(O)OCH2CH2CH2*CH2CH2S278*C(O)OCH2*CH2CH2NH*CH2CH2O279*C(O)OCH2*CH2CH2NH*CH2CH2CH2O280*C(O)OCH2CH2CH2281*C(O)OCH2CH2CH2CH2282*C(O)NHCH2CH2*CH2CH2NH283*C(O)NHCH2CH2CH2*CH2CH2NH284*C(O)NHCH2*CH2CH2NH*CH2CH2O285*C(O)NHCH2*CH2CH2S286*C(O)NHCH2CH2*CH2CH2NH287*C(O)NHCH2CH2*CH2CH2O288*C(O)NHCH2CH2*CH2CH2S289*C(O)NH*CH2CH2NH*CH2CH2O290*C(O)OCH2*CH2CH2S291*C(O)OCH2CH2*CH2CH2S292*C(O)CH2OCH2*CH2CH2NH293*C(O)CH2OCH2CH2*CH2CH2C(O)NH294*C(O)CH2OCH2CH2*CH2CH2O295*C(O)CH2OCH2CH2*CH2CH2NH296*C(O)CH2NH*CH2CH2O*CH2CH2S297*C(O)CH2NH*CH2CH2O*CH2CH2O298*C(O)CH2NHCH2CH2*CH2CH2NH299CH2*CH2CH2O*CH2CH2OThe invention also provides methods for preparing compounds represented by Formula (I), Formula (I-1-P1), Formula (I-1-P2), Formula (I-1-P3), Formula (I-1-P4), Formula (I-2), Formula (I-3), Formula (I′-1), (I′-2), (I′-3), Formula (II), Formula (II-A), Formula (II-A′), Formula (II-B), Formula (II-B′), Formula (II-C), Formula (II-C′), Formula (III), Formula (III-1), Formula (III-2), Formula (III-1-1), Formula (III-2-1), Formula (III-A), Formula (III-A′), Formula (III-B), Formula (III-B′), Formula (III-B′-1), Formula (III-C), Formula (III-C′), Formula (III-D), Formula (III-D′), Formula (III-E), Formula (III-E′), Formula (IV), Formula (A), Formula (B), Formula (B-1), Formula (C), Formula (C-1), Formula (D), Formula (D-1), Formula (B-2), Formula (B-3), Formula (C-2), Formula (C-3), Formula (D-2), Formula (D-3), Formula (E), Formula (F), Formula (E-1), Formula (E-2), Formula (E-3), Formula (E-4), Formula (F-1), Formula (F-2), Formula (G), Formula (G-1), Formula (G-2), Formula (G-3), Formula (G-4), Formula (H), Formula (H-1), Formula (H-2), Formula (H-3), Formula (H-4), Formula (D-c), Formula (D-f),Formula (D-g), and Formula (D-h), or pharmaceutically acceptable salts thereof.The compounds of the general formulas mentioned can be prepared by a variety of methods, including but not limited to the following methods:wherein, each of Y1 and Y2 is independently halogen (i.e. F, Cl, Br), preferably Br; Y is independently halogen (i.e. F, Cl, Br) or oxo (The “oxo” refers to the ═O of —C(O)H), preferably Br or oxo (The “oxo” refers to the ═O of —C(O)H); R′ is defined as in the compounds of Formula (II), W1, W2, and W3 are defined as in the compounds of Formula (I), Formula (I-1-P1), Formula (I-1-P2), Formula (I-1-P3), Formula (I-1-P4) and Formula (I-1);Under the action of a base, Compound (a) and Compound (b) are reacted at room temperature for 16 h to obtain Compound (c), Compound (c) is hydrolyzed under alkaline conditions of hydrogen peroxide, and then esterified to obtain Intermediate (d), which is subjected to carbonyl insertion under atmospheric pressure to obtain Intermediate (e). DIBAL-H reduction gives Intermediate (f), and Intermediate (f) is subjected to reductive amination in a tetrahydrofuran solution of ammonia to obtain Intermediate (g). The intermediate is further subjected to reductive amination or substitution reaction to obtain Intermediate (i), and deprotection under acidic conditions gives the compound of Formula (II-A′); Intermediate (g) and Intermediate (f) undergo a substitution reaction or reductive amination to give Intermediate (j) which is deprotected under acidic conditions to give a compound of Formula (III-C′).Y3 is independently halogen (i.e. F, Cl, Br) or oxo (The “oxo” refers to the ═O of —C(O)H), preferably Br or oxo (The “oxo” refers to the ═O of —C(O)H), L3 is defined as in the compounds of Formula (I) Formula (I-1-P1), Formula (I-1-P2), Formula (I-1-P3), Formula (I-1-P4) and Formula (I-1); Compound (k) is synthesized according to the conditions of patent CN114008021A, Compound (m) is obtained from Compound (k) and Compound (1) by reductive amination or substitution reaction, and then deprotected under acidic conditions to obtain a compound of Formula (III-A′).wherein, W1, W2, W3 are defined as in the compounds of Formula (I) Formula (I-1-P1), Formula (I-1-P2), Formula (I-1-P3), Formula (I-1-P4) and Formula (I-1);In the tetrahydrofuran solution of ammonia, Compound (p) is obtained by reductive amination of Compound (q); Compound (q) and Compound(s) are further subjected to reductive amination to obtain Intermediate (t); Intermediate (t) is deprotected under acidic conditions to obtain a compound of Formula (III-D′).wherein, Z11, Z12, Z22, Z32, X, X1, X2, n, n1, n2, n3, and rings W1, W2, and W3 are defined as in compounds of Formula (I), Formula (I-1-P1), Formula (I-1-P2), Formula (I-1-P3), Formula (I-1-P4), and Formula (D), each of Pg1 and Pg2 is independently a protecting group. Preferably, Pg1 is independently selected from tert-butyl, methyl, and benzyl, and Pg2 is independently selected from tert-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (FMOC), andbenzyloxycarbonyl (Cbz), preferably Boc.The invention also provides a pharmaceutical composition comprising the compounds of the invention, or pharmaceutically acceptable salts thereof.

[0434] The invention also provides a pharmaceutical composition comprising the compounds of the invention, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients thereof.

[0435] In the above-mentioned pharmaceutical composition, the compound of the present invention, or a pharmaceutically acceptable salt thereof accounts for 0.1-99.9 wt % of the pharmaceutical composition, for example, 0.5 wt %, 1 wt %, 2 wt %, 3 wt %, 4 wt %, 5 wt %, 6 wt %, 7 wt %, 8 wt %, 9 wt %, 10 wt %, 20 wt %, 30 wt %, 40 wt %, 50 wt %, 60 wt %, 70 wt %, 80 wt %, 90 wt %, 91 wt %, 92 wt %, 93 wt %, 94 wt %, 95 wt %, 96 wt %, 97 wt %, 98 wt %, 99 wt %, 99.5 wt %, or a range formed by the combination of any two of the above-mentioned point values, and the balance is a pharmaceutically acceptable excipient.

[0436] In some embodiments of the invention, the pharmaceutical composition is used for an inhibitor of Lp(a) assembly.

[0437] In some embodiments of the invention, the pharmaceutical composition is used for a medicament for treating cardiovascular diseases (CVD).

[0438] The compounds shown in the invention, or pharmaceutically acceptable salts thereof may be carried out in pure form or in the form of a suitable pharmaceutical composition by providing any acceptable mode of administration of a medicament for similar use. The pharmaceutical composition of the invention may be prepared by combining the compounds of the invention with suitable pharmaceutically acceptable excipients. The pharmaceutical composition of the invention may be formulated as solid, semi-solid, liquid or gaseous formulations. In general, the above pharmaceutical composition may be prepared by conventional preparative methods using vehicles conventional in the field of formulations.

[0439] The invention also provides the use of the compounds of the invention, or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for preventing and / or treating cardiovascular diseases (CVD).

[0440] In one embodiment of the invention, it provides the use of the compounds of the invention, or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for preventing and / or treating diseases or conditions associated with elevated blood plasma Lp(a) levels.

[0441] In one embodiment of the invention, diseases or conditions associated with elevated blood plasma Lp(a) levels are cardiovascular diseases (CVD), including, but not limited to atherosclerotic cardiovascular disease (ASCVD), coronary artery stenosis, coronary artery-related diseases, aortic valve stenosis, aortic valve stenosis-related diseases, heart failure, heart failure-related diseases, atrial fibrillation, and atrial fibrillation-related diseases; said ASCVD includes peripheral vascular disease, peripheral artery-related diseases, coronary heart disease, ischemic stroke, and ischemic stroke-related diseases.

[0442] The term “elevated blood plasma Lp(a) level” refers to a blood plasma level equal to or above a normal level, and for human beings, “elevated blood plasma level of Lp(a)” refers to a blood plasma level equal to or above about 30 mg / dL.

[0443] In one embodiment of the present invention, for human beings, the term “elevated blood plasma Lp(a) level” refers to blood plasma levels ≥about 50 mg / dL. The compounds provided herein can be used in therapy to reduce blood plasma levels of Lp(a).

[0444] The invention also provides the use of the compounds of the invention, or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for preventing and / or treating of diseases mediated by Lp(a).

[0445] Moreover, the invention provides the use, wherein diseases mediated by Lp(a) are cardiovascular diseases (CVD).

[0446] Furthermore, the invention provides the use, wherein said cardiovascular diseases (CVD) are selected from atherosclerotic cardiovascular disease (ASCVD), coronary artery stenosis, coronary artery-related diseases, aortic valve stenosis, aortic valve stenosis-related diseases, heart failure, heart failure-related diseases, atrial fibrillation, and atrial fibrillation-related diseases; said ASCVD includes peripheral vascular disease, peripheral artery-related diseases, coronary heart disease, ischemic stroke, and ischemic stroke-related diseases.

[0447] The invention also provides a method for preventing and / or treating cardiovascular diseases, comprising administering to a patient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt of the compound or a pharmaceutical composition of the invention.

[0448] In one embodiment of the invention, it provides a method of preventing and / or treating diseases or conditions associated with elevated blood plasma Lp(a) levels, comprising administering to a patient a therapeutically effective amount of the compounds of the invention, or pharmaceutically acceptable salts thereof or pharmaceutical composition of the invention. In one embodiment of the invention, diseases or conditions associated with elevated blood plasma Lp(a) levels are cardiovascular diseases (CVD), including, but not limited to atherosclerotic cardiovascular disease (ASCVD), coronary artery stenosis, coronary artery-related diseases, aortic valve stenosis, aortic valve stenosis-related diseases, heart failure, heart failure-related diseases, atrial fibrillation, and atrial fibrillation-related diseases; said ASCVD includes peripheral vascular disease, peripheral artery-related diseases, coronary heart disease, ischemic stroke, and ischemic stroke-related diseases.

[0449] The invention also provides a method for preventing and / or treating diseases mediated by Lp(a), comprising administering to a patient a therapeutically effective amount of the compounds of the invention, or pharmaceutically acceptable salts thereof or pharmaceutical composition of the invention; preferably, diseases mediated by Lp(a) are cardiovascular diseases (CVD), including, but not limited to atherosclerotic cardiovascular disease (ASCVD), coronary artery stenosis, coronary artery-related diseases, aortic valve stenosis, aortic valve stenosis-related diseases, heart failure, heart failure-related diseases, atrial fibrillation, and atrial fibrillation-related diseases; said ASCVD includes peripheral vascular disease, peripheral artery-related diseases, coronary heart disease, ischemic stroke, and ischemic stroke-related diseases.

[0450] Further, the invention provides a use or method, wherein the compounds of the invention, or pharmaceutically acceptable salts thereof may be administered in combination with another compound for treating or preventing diseases mediated by Lp(a) such as cardiovascular diseases (CVD).

[0451] The invention also provides a compound of the invention, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the invention for preventing and / or treating cardiovascular diseases.

[0452] The invention also provides a compound of the invention, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the invention for use in medicament.

[0453] The invention provides a compound of the invention, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the invention for use in preventing and / or treating cardiovascular disease. The invention provides a compound of the invention, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the invention for use in preventing and / or treating diseases or conditions associated with elevated blood plasma Lp(a) levels. In one embodiment of the invention, the diseases or conditions associated with elevated blood plasma Lp(a) levels are cardiovascular diseases (CVD), including, but not limited to atherosclerotic cardiovascular disease (ASCVD), coronary artery stenosis, coronary artery-related diseases, aortic valve stenosis, aortic valve stenosis-related diseases, heart failure, heart failure-related diseases, atrial fibrillation, and atrial fibrillation-related diseases; said ASCVD includes peripheral vascular disease, peripheral artery-related diseases, coronary heart disease, ischemic stroke, and ischemic stroke-related diseases.

[0454] The invention also provides a compound of the invention, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the invention for use in preventing and / or treating diseases mediated by Lp(a); preferably, the diseases mediated by Lp(a) are cardiovascular diseases (CVD); further preferably, the cardiovascular diseases (CVD) include, but are not limited to atherosclerotic cardiovascular disease (ASCVD), coronary artery stenosis, coronary artery-related diseases, aortic valve stenosis, aortic valve stenosis-related diseases, heart failure, heart failure-related diseases, atrial fibrillation, and atrial fibrillation-related diseases; said ASCVD includes peripheral vascular disease, peripheral artery-related diseases, coronary heart disease, ischemic stroke, and ischemic stroke-related diseases.

[0455] In one embodiment of the invention, it provides a compound of the invention, or a mixture thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the invention, for preventing and / or treating diseases or conditions associated with elevated blood plasma Lp(a) levels. In one embodiment of the invention, the diseases or conditions associated with elevated blood plasma Lp(a) levels are cardiovascular diseases (CVD), including, but not limited to atherosclerotic cardiovascular disease (ASCVD), coronary artery stenosis, coronary artery-related diseases, aortic valve stenosis, aortic valve stenosis-related diseases, heart failure, heart failure-related diseases, atrial fibrillation, and atrial fibrillation-related diseases; said ASCVD includes peripheral vascular disease, peripheral artery-related diseases, coronary heart disease, ischemic stroke, and ischemic stroke-related diseases.

[0456] In a further aspect, this application provides a compound of the invention, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the invention for the preventing and / or treating diseases mediated by Lp(a); preferably, the diseases mediated by Lp(a) are cardiovascular diseases (CVD); further preferably, the cardiovascular diseases (CVD) are selected from atherosclerotic cardiovascular disease (ASCVD), coronary artery stenosis, coronary artery-related diseases, aortic valve stenosis, aortic valve stenosis-related diseases, heart failure, heart failure-related diseases, atrial fibrillation, and atrial fibrillation-related diseases; said ASCVD includes peripheral vascular disease, peripheral artery-related diseases, coronary heart disease, ischemic stroke, and ischemic stroke-related diseases.

[0457] The use of the compounds of the invention, or pharmaceutically acceptable salts thereof in the manufacture of a medicament for preventing and / or treating cardiovascular diseases in combination with another compound for preventing and / or treating cardiovascular diseases.

[0458] In one embodiment of the invention, cardiovascular diseases are diseases or conditions associated with elevated blood plasma Lp(a) levels.

[0459] In one embodiment of the invention, the diseases or conditions associated with elevated blood plasma Lp(a) levels are cardiovascular diseases (CVD), including, but not limited to atherosclerotic cardiovascular disease (ASCVD), coronary artery stenosis, coronary artery-related diseases, aortic valve stenosis, aortic valve stenosis-related diseases, heart failure, heart failure-related diseases, atrial fibrillation, and atrial fibrillation-related diseases; said ASCVD includes peripheral vascular disease, peripheral artery-related diseases, coronary heart disease, ischemic stroke, and ischemic stroke-related diseases.

[0460] The compounds of the invention, or pharmaceutically acceptable salts thereof are for use in preventing and / or treating cardiovascular diseases in combination with other compounds. Moreover, the another compound is for preventing and / or treating cardiovascular diseases. Moreover, the cardiovascular diseases are diseases or conditions associated with elevated blood plasma Lp(a) levels. Moreover, the disease or condition associated with elevated blood plasma Lp(a) levels includes, but is not limited to atherosclerotic cardiovascular disease (ASCVD), coronary artery stenosis, coronary artery-related diseases, aortic valve stenosis, aortic valve stenosis-related diseases, heart failure, heart failure-related diseases, atrial fibrillation, and atrial fibrillation-related diseases; said ASCVD includes peripheral vascular disease, peripheral artery-related diseases, coronary heart disease, ischemic stroke, and ischemic stroke-related diseases.

[0461] A compound of the invention or a pharmaceutically acceptable salt thereof can be co-applied with a therapeutic method. In certain embodiments, the therapeutic method may be, but is not limited to, Lp(a) plasmapheresis. The drug or therapeutic method may be co-applied or simultaneously applied.

[0462] The drug or therapeutic method may be applied sequentially or subsequently.

[0463] The invention also provides a pharmaceutical composition, comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and another compound for treating or preventing diseases mediated by Lp(a); preferably, diseases mediated by Lp(a) are for example, cardiovascular diseases (CVD).

[0464] When the compounds of the invention or pharmaceutically acceptable salts thereof are administered in combination with an additional therapeutic agent for treating a disease such as a CVD, the compounds of the invention, or pharmaceutically acceptable salts thereof may provide a more effective therapeutic effect for cardiovascular-related diseases.Definition

[0465] The term “optional”, “arbitrary”, “optionally” or “arbitrarily” and the like means that the subsequently described event or circumstance may but does not necessarily occur, and that the description includes instances where the event or circumstance mentioned occurs and instances where it does not occur.

[0466] The “more” in “optionally substituted with one or more substituents independently selected from . . . ” refers to 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; preferably 1, 2, 3 or 4; more preferably 1 or 2. When “about” is used to describe molecular weight, the word “about” indicates rounding. Unless otherwise specified, the term “alkyl” refers to a monovalent saturated aliphatic hydrocarbon group, a linear or branched group comprising from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms (i.e., C1-10alkyl), further preferably from 1 to 8 carbon atoms (C1-8alkyl), and more preferably from 1 to 6 carbon atoms (i.e., C1-6alkyl). For example, “C1-6alkyl” means that the group is an alkyl group and the number of carbon atoms on the carbon chain is between 1 to 6 (specifically 1, 2, 3, 4, 5 or 6). The examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, and n-octyl. Unless otherwise specified, the term “alkylene” refers to a monovalent saturated aliphatic hydrocarbon group, including straight or branched groups containing 1-20 carbon atoms, preferably containing 1-10 carbon atoms (i.e., C1-10alkylene), more preferably containing 1-8 carbon atoms (C1-8alkylene), and even more preferably containing 1-6 carbon atoms (i.e., C1-6alkylene). For example, “C1-6alkylene” refers to an alkylene group, and the number of carbon atoms on the carbon chain is between 1-6 (specifically 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methylene, ethylene, n-propylene, n-pentylene, n-hexylene, and

[0467] Unless otherwise specified, the term “alkenyl” refers to a straight or branched chain unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and with at least one double bond. Alkenyl may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C2-10alkenyl), more preferably 2-8 carbon atoms (C2-8-alkenyl), and even more preferably 2-6 carbon atoms (i.e., C2-6alkenyl), 2-5 carbon atoms (i.e., C2-8-alkenyl), 2-4 carbon atoms (i.e., C2-4alkenyl), 2-3 carbon atoms (i.e., C2-3alkenyl), and 2 carbon atoms (i.e., C2alkenyl). For example, “C2-6alkenyl” refers to an alkenyl group, and the number of carbon atoms on the carbon chain is between 2-6 (specifically 2, 3, 4, 5, or 6). Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, and 1,3-butadienyl.

[0468] Unless otherwise specified, the term “alkynyl” refers to a straight or branched chain unsaturated aliphatic hydrocarbon group with at least one triple bond composed of carbon atoms and hydrogen atoms. Alkynyl may contain 2-20 carbon atoms, preferably contains 2-10 carbon atoms (i.e., C2-10alkynyl), more preferably contains 2-8 carbon atoms (C2-5alkynyl), even more preferably contains 2-6 carbon atoms (i.e., C2-6alkynyl), 2-5 carbon atoms (i.e., C2-5alkynyl), 2-4 carbon atoms (i.e., C2-4alkynyl), 2-3 carbon atoms (i.e., C2-3alkynyl), and 2 carbon atoms (i.e., Czalkynyl). For example, “C2-6alkynyl” refers to an alkynyl group, and the number of carbon atoms on the carbon chain is between 2-6 (specifically 2, 3, 4, 5, or 6). Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl.

[0469] Unless otherwise specified, the term “cycloalkyl” refers to a monocyclic, bicyclic or polycyclic cyclic saturated aliphatic hydrocarbon group with a specified number of carbon atoms, preferably containing 3-14 carbon atoms (i.e., C3-14cycloalkyl), preferably containing 4-14 carbon atoms (i.e., C4-14cycloalkyl), preferably containing 5-14 carbon atoms (i.e., C5-14cycloalkyl), more preferably containing 6-14 carbon atoms (C6-14cycloalkyl), and further preferably 6-12 carbon atoms (C6-12cycloalkyl). The examples include, but are not limited to, cyclohexyl and spiro[3.5]nonyl. Unless otherwise specified, the term “oxaalkyl” refers to an alkyl residue in which one or more carbons (and their associated hydrogens) are replaced by oxygen, such as “alkoxy”, “alkoxyalkyl”.

[0470] For example, C3oxaalkylene includes —OC1-3alkoxy, —CH2OCH2CH3, —CH2CH2OCH3, etc. The examples include methoxy, ethoxy, propoxy and methoxypropyl. The term oxaalkyl has as its ordinary meaning as understood in the field [See Nomenclature of Organic Compounds: Principles and Practice, published by the American Chemical Society, 196, but not limited to 127 (a)], that is, it refers to compounds in which the oxygen is bonded to its adjacent atom by a single bond (forming an ether bond); it does not refer to double-bond oxygen found in carbonyl groups. The terms “thiaalkyl” and “selenaalkyl” are similar to “oxaalkyl”. The term “azaalkyl” refers to an alkyl group containing atomic groups “NH” or “—N(C1-3alkyl)—”, e.g., C3azaalkylene includes —NHCH2CH2CH3, —CH2NHCH2CH3, —CH2CH2NHCH3, —CH2CH2N(CH3)CH3, etc.

[0471] “Alkoxy” means-O-alkyl, defined hereinabove, that is, comprising 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-8 carbon atoms, and even more preferably 1-6 carbon atoms (specifically 1, 2, 3, 4, 5 or 6). The examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, and 1-ethylpropoxy.

[0472] Unless otherwise specified, the term “halogen” or “halo / halogenated” refers to F, Cl, Br, or I. Unless otherwise specified, the term “heterocyclic / heterocyclyl” refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic hydrocarbon substituent that is nonaromatic and contains from 3 to 20 ring atoms, of which 1, 2, 3 or more ring atoms are selected from N, O or S, and the remaining ring atoms are C. Preferably it includes 3-12 ring atoms, further preferably 3-10 ring atoms, or 3-8 ring atoms, or 3-6 ring atoms, or 4-6 ring atoms, or 5-6 ring atoms. Heteroatoms are preferably 1-4, more preferably 1-3 (that is, 1, 2 or 3). The examples of monocyclic heterocyclics include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, pyranyl, etc. Bicyclic or polycyclic heterocyclic groups include heterocyclic groups of spiro, fused, and bridged rings.

[0473] Unless otherwise specified, the term “aryl” means an aromatic carbon ring system containing 6-16 carbon atoms, or 6-14 carbon atoms, or 6-12 carbon atoms, or a monocyclic, bicyclic and tricyclic ring of 6-10 carbon atoms, preferably 6-10 carbon atoms, and the term “aryl” may be used interchangeably with the term “aromatic ring”. The examples of aryl groups may include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, or pyrenyl.

[0474] Unless otherwise specified, the term “heteroaryl” means an aromatic monocyclic, bicyclic or polycyclic ring system containing 5-16 membered structures, or 5-14 membered structures, 5-12 membered structures, 5-10 membered structures, 5-8 membered structures, wherein 1, 2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms are independently selected from O, N or S, and the number of heteroatoms is preferably 1, 2 or 3. Polycyclic heteroaryl is fused heteroaryl. The examples of heteroaryl groups may include, but are not limited to, furanyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiadiazinyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzoylpyridinyl, benzopyrimidinyl, quinoxalinyl, benzimidazoyl, benzophthalazinyl, pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, and [1,2,4]triazolo[1,5-a]pyridinyl.

[0475] Unless otherwise specified, the term “fused heteroaryl” refers to an aromatic ring system formed by two or more cyclic structures sharing two adjacent atoms with each other, each ring in the fused heteroaryl being an unsaturated aromatic ring, which may contain 5-20 ring atoms, preferably 6-14 ring atoms, more preferably 7-10 ring atoms, containing 1-4 cyclic heteroatoms, preferably 1-3 (that is, 1, 2 or 3) ring heteroatoms, and the heteroatoms are independently selected from N, O and S. Fused heteroaryl groups include bicyclic, tricyclic, tetracyclic or polycyclic fused heteroaryl, preferably bicyclic, tricyclic or tetracyclic fused heteroaryl, more preferably bicyclic or tricyclic fused heteroaryl. The examples of fused heteroaryl groups include (but are not limited to)etc.Unless otherwise specified, the term “pharmaceutically acceptable salt(s)” refers to salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals, particularly humans, irritation, allergic response, etc., and are commensurate with a reasonable benefit / risk ratio, such as medically acceptable salts of amines, carboxylic acids, and other types of compounds, which are well known in the field. The salt may be prepared in situ during the final isolation and purification of the compounds of the invention or by reacting the free base or free acid with a suitable reagent alone.

[0477] The compounds of the present invention and pharmaceutically acceptable salts also include “stereoisomers” thereof. Unless otherwise specified, the term “stereoisomer” refers to a compound with the same chemical structure but with different spatially arranged atoms or groups. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans-isomerism), atropisomers, etc. Any obtained mixtures of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers, for example, by chromatography and / or fractional crystallization. Compounds and salts described in this specification may include one or more chiral (i.e., asymmetric) centers. To the extent a structure or chemical name in this specification does not indicate the chirality, the structure or name is intended to encompass any single stereoisomer (i.e., any single chiral isomer) corresponding to that structure or name, as well as any mixture of stereoisomers (e.g., a racemate). In some embodiments, a single stereoisomer is obtained by isolating it from a mixture of isomers (e.g., a racemate) using, for example, chiral chromatographic separation. In other embodiments, a single stereoisomer is obtained through direct synthesis from, for example, a chiral starting material.

[0478] A particular enantiomer of a compound described herein may be more active than other enantiomers of the same compound. In one embodiment, the compound, or a pharmaceutically acceptable salt thereof, is a single enantiomer being in an enantiomeric excess (% ee) of ≥90%, ≥95%, ≥96%, ≥ 97%, ≥98%, or ≥99%. In one aspect, the single enantiomer is present in an enantiomeric excess (% ee) of ≥99%.

[0479] A particular diastereoisomer of a compound described herein may be more active than other diastereoisomers of the same compound. In one embodiment, the compound, or a pharmaceutically acceptable salt thereof, is a single diastereoisomer being in a diastereomeric excess (% de) of ≥90% ≥95%, ≥96%, ≥97%, ≥98%, or ≥99%. In one aspect, the single diastereomer is present in an diastereomeric excess (% de) of ≥99%.

[0480] The compounds of the invention and pharmaceutically acceptable salts thereof also include their “Tautomers”. Compounds and salts described in this specification may exist in various tautomeric forms. “Tautomers” are structural isomers that exist in equilibrium resulting from the migration of a hydrogen atom. Unless otherwise specified, the term “tautomer” refers to structural isomers with different energies that can be interconverted by low energy barriers. If tautomerism is possible (e.g. in solution), the chemical equilibrium of the tautomer can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversion via proton migration such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by the reorganization of some of the bonding electrons.

[0481] The compounds of the invention and pharmaceutically acceptable salts thereof also include their “isotopic derivatives”. Unless otherwise specified, the term “isotopic derivative” refers to a compound of the invention that may exist in an isotopically labelled or enriched form containing one or more atoms with an atomic mass or mass number different from the atomic mass or mass number of the atom which is present in the greatest abundance in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes that are typically used as isotopic labels include isotopes of hydrogen, 2H and 3H; isotopes of carbon: 13C and 14C; isotopes of chlorine: 35Cl and 37Cl; isotopes of fluorine: 18F; isotopes of iodine: 123I and 125I; isotopes of nitrogen: 13N and 15N; isotopes of oxygen: 15O, 17O and 18O and isotopes of sulfur 35S. These isotopically labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. Especially 3H and 13C, are more widely used because they are easy to label and easy to detect. Substitution of certain heavy isotopes, such as heavy hydrogen (2H), enhances metabolic stability, prolongs half-life, and thus provides therapeutic advantages for dose reduction. Isotopically labeled compounds generally begin with labeled starting materials and are synthesized using known synthetic techniques like non-isotopically labeled compounds. All compounds disclosed herein, including general formula compounds and specific compounds, where an atom is replaced by one or more of its isotopes (for example a compound of Formula (I) where one or more carbon atoms is an 11C or 13C carbon isotope, or where one or more hydrogen atoms is a 2H or 3H isotope), are encompassed herein.

[0482] Unless otherwise specified, the compounds of the invention and pharmaceutically acceptable salts thereof also include their “solvates”. The term “solvate” refers to the physical association of a compound of the invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonds. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to be separated. Solvent molecules in solvates may be present in regular and / or disordered order. Solvates may contain stoichiometric or non-stoichiometric solvent molecules. “Solvate” covers the solution phase and separable solvates. The examples of solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the field. The term “hydrate” refers to a substance in which a water molecule binds to a cation or anion in a compound by a coordination bond or a covalent bond, or refers to a substance in which the water ion does not bind directly to a cation or anion but is present in a certain proportion at a defined position in the solid lattice.

[0483] Unless otherwise specified, the compounds of the invention and pharmaceutically acceptable salts thereof also include their “prodrugs”. The term “prodrug” refers to a drug that is converted in vivo to a parent drug. Prodrugs are usually useful as they can improve certain determined and undesirable physical or biological properties. Physical properties are usually relevant solubility (excessive or insufficient lipid or water solubility) or stability, while problematic biological characteristics include rapid metabolism or poor bioavailability, which may themselves be related to physicochemical properties, for example, they can be bioavailable through oral administration, whereas the parent compound cannot. The solubility of the prodrug in the pharmaceutical composition is also improved compared to the parent drug. An example of, but not limited to, a prodrug of the invention may be any compound of the invention administered as an ester (“prodrug”) to facilitate transmission across the cell membrane, where water solubility is detrimental to mobility, but once it enters the intracellular water solubility is beneficial, which is subsequently metabolically hydrolyzed to a carboxylic acid, the active entity. Another example of a prodrug may be a short peptide (polyamino acid) bound to an acid moiety in which the peptide is metabolized to show an active moiety.

[0484] The term “oxo” refers to the replacement of two H at the same substitution position by one O to form a double bond.

[0485] The term “thio” refers to the replacement of two H at the same substitution position by one S to form a double bond.

[0486] The term “therapeutically effective amount” refers to the amount of a compound or combination of compounds that provides the intended clinical or therapeutic benefit in the subject being treated. The therapeutically effective amount will depend on the general condition of the subject being treated (e.g., weight, age and sex), the severity of the disease, the specific compound being administered, the dosing regimen, the use of concomitant medications and other factors, and can be determined by the prescribing physician in accordance with routine practice. For example, the pharmaceutical composition can be administered at a dose appropriate for the disease to be treated (or prevented), such as administering about 0.5 μg to about 50 mg of at least one compound / kg of subject body weight, preferably about 10 μg to about 100 mg / kg of body weight / day.

[0487] The term “pharmaceutically acceptable excipient” refers to a carrier that does not cause significant irritation to an organism and does not eliminate the biological activity and properties of the administered compound. Any commonly used pharmaceutically acceptable carrier may be used, the selection of which depends on factors such as the specific mode of administration, the effect of the carrier on solubility and stability, and the nature of the dosage form and is within the ordinary skills of those skilled in the art. Examples of the pharmaceutically acceptable excipient include, but are not limited to, diluents, excipients, fillers, binders, wetting agents, disintegrants, lubricants, colorants, fragrances, absorption promoters, surfactants, adsorption carriers, etc. which are conventional in the pharmaceutical field.

[0488] Unless otherwise specified, the term “treatment” encompasses any treatment of a patient's disease, disorder, and condition, including: (a) inhibiting a disease, disorder, or condition, i.e., arresting its development; or (b) relief of symptoms of a disease, condition and condition, that is, leading to resolution of a disease or symptoms; or (c) ameliorating or eliminating a disease, disorder and condition or one or more symptoms associated with the disease.

[0489] Abbreviations used in the preparation examples, examples, and elsewhere herein are:

[0490] THF: tetrahydrofuran; Dioxane: 1,4-dioxane; FA: formic acid; PE: petroleum ether; EA: ethyl acetate; DCM: dichloromethane; TFA: trifluoroacetic acid; XPhos Pd G2: Chloro (2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl) [2-(2′-amino-1,1′-biphenyl)]palladium (II).

[0491] The beneficial effects of the invention are one or more of the following:

[0492] The invention designs a class of compounds with novel structures, providing a new direction for the development of drugs that reduce plasma Lp(a) levels. In vitro activity studies showed that the compound of the invention had strong inhibitory effects on Lp(a) assembly; the compound of the invention had good pharmacokinetic properties; safety evaluation experiments showed that the compound of the invention had excellent safety; in vivo pharmacodynamic experiments in mice showed that the compound of the invention significantly reduced serum Lp(a) levels and therefore could be used as a promising compound for the treatment of diseases mediated by Lp(a). In addition, the invention investigated a specific synthesis method, which is simple in process, convenient in operation, and is advantageous for large-scale industrial production and application.DETAILED DESCRIPTION OF THE INVENTION

[0493] The invention is further elaborated below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the invention only and not to limit the scope of the invention. Experimental methods without specific conditions are indicated in the following examples, usually under conventional conditions or as recommended by the manufacturer. All professional and scientific terms used herein have the same meaning as those familiar to professionals in the field, unless otherwise defined. In addition, any method and material similar to or equal to what has been described can be applied to the method of the invention. The preferred implementation methods and materials shown in the text are for demonstration purposes only.

[0494] The structures of the compounds of the invention are determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS) or / and high-performance liquid chromatography (HPLC). NMR was determined using Bruker 400 MHz or / and Varian 400 MHz; LC-MS was performed using Agilent, 1260 Infinity II-6120 / 6125MSD; HPLC was performed using Waters UPCC (CA-352).

[0495] The starting materials used in the examples of the invention are either known and commercially available or can be synthesized by methods known in the field or by analogy therewith.

[0496] The invention provides the methods of preparing the compounds. The compounds can be prepared by the following steps.Synthesis of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (Intermediate 1-5)Step 1: Synthesis of tert-butyl (R)-3-(2-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl) pyrrolidine-1-carboxylate (Intermediate 1-1)

[0497] Triethylamine (11.03 g, 109.04 mmol, 2.5 eq) was added to a solution of (R)-2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl) acetic acid (10 g, 43.62 mmol, 1 eq) in tetrahydrofuran (150 mL) maintained at 10° C. After 5 min, pivaloyl chloride (6.57 g, 54.52 mmol, 1.25 eq) was added. After 15 min, lithium chloride (2.31 g, 54.52 mmol, 1.25 eq) and(S)-4-benzyloxazolidin-2-one (7.73 g, 43.62 mmol, 1 eq) in tetrahydrofuran (50 mL) were added. The mixture was warmed to room temperature and stirred for 24 h. After 24 h 1N HCl aqueous solution (50 mL) was added and the organic phase was separated from the aqueous phase. The organic phase was washed with 1N aqueous sodium hydroxide (50 mL) and saturated aqueous NaCl solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and purified by rapid chromatography (silica gel, petroleum ether:ethyl acetate=5:1, v / v) to give the target compound (15g). LCMS(ESI)[M+H]+=332.7. 1HNMR (400 MHZ, CDCl3) δ 7.38-7.27 (m, 3H), 7.23-7.17 (m, 2H), 4.68 (ddd, J=10.8, 7.2, 3.2 Hz, 1H), 4.26-4.16 (m, 2H), 3.68 (dd, J=10.8, 7.2 Hz, 1H), 3.48 (ddd, J=11.6, 8.4, 3.6 Hz, 1H), 3.37-3.23 (m, 2H), 3.12-2.94 (m, 3H), 2.78 (dd, J=13.2, 9.6 Hz, 1H), 2.67 (dt, J=14.8, 7.2 Hz, 1H), 2.17-2.06 (m, 1H), 1.63-1.55 (m, 1H), 1.46 (d, J=4.4 Hz, 9H).Step 2: Synthesis of tert-butyl (R)-3-((S)-1-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(3-bromophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (Intermediate 1-2)

[0498] Under nitrogen protection, a solution of lithium bis(trimethylsilyl)amide (1M in THF, 30.1 mL, 30.1 mmol, 1 eq) was added dropwise to a solution of tert-butyl (R)-3-(2-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl) pyrrolidine-1-carboxylate (12 g, 30.89 mmol, 1 eq) in tetrahydrofuran (100 mL) at 0° C. The mixture was stirred at 0° C. for 30 min, then a solution of 1-bromo-3-(bromomethyl)benzene (8.49 g, 33.98 mmol, 1.1 eq) in tetrahydrofuran (20 mL) was added slowly, and the reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was cooled using an ice-water bath, a saturated aqueous solution of ammonium chloride was added, water was added to the mixture and extracted with ethyl acetate, and then the organic layer was washed with saturated aqueous sodium chloride. The organic matter was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the target compound (17g). LCMS(ESI)[M-tert-butyl+H]+=501.1.Step 3: Synthesis of(S)-3-(3-bromophenyl)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)propanoic acid (Intermediate 1-3)

[0499] A solution of hydrogen peroxide (0.88 M in water, 3.4 mL, 32.3 mmol, 1.5 eq) was added in one portion to a solution of tert-butyl (R)-3-((S)-1-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(3-bromophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (12 g, 21.53 mmol, 1 eq) in tetrahydrofuran (120 mL), cooled with an ice / water bath, followed by adding a solution of lithium hydroxide monohydrate (0.77 g, 32.3 mmol, 1.5 eq) in water (10 mL), and the reaction temperature was raised to room temperature and stirred for 2.5 h. The reaction mixture was cooled to 0° C. and a solution of sodium bisulfite (4.1 g) in water (20 mL) was added, followed by adding a solution of sodium hydroxide in water (5N) to adjust the pH of the reaction mixture to >12. Then water and methyl tert-butyl ether were added to separate the layers and the aqueous layer was extracted with methyl tert-butyl ether. The combined organics were extracted with water, and then this aqueous extract was added to the main aqueous solution, the aqueous solution was stirred with methyl tert-butyl ether (100 mL) and the mixture was cooled to 0° C., hydrochloric acid (5N) was added to adjust the pH of the solution to 3; the layers were separated and the organic layer was washed with a mixture of water and saturated aqueous NaCl solution; the organic matter was dried over anhydrous sodium sulfate, filtered, and concentrated to give the target compound (5.5 g). LCMS(ESI)[M-tert-butyl+H]+=341.6.Step 4: Synthesis of tert-butyl (R)-3-((S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl) pyrrolidine-1-carboxylate (Intermediate 1-4)

[0500] (S)-3-(3-bromophenyl)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)propanoic acid (5.5 g, 13.81 mmol, 1 eq) was dissolved in 2-methyltetrahydrofuran (80 mL). Under nitrogen protection, tert-butyl N,N′-diisopropylcarbamimidate (13.83 g, 69.05 mmol, 5 eq) was added, and the mixture was heated to 65° C. and stirred for 16 h. The insoluble materials were filtered off, the filter cake was washed with methyl tert-butyl ether. The filtrate was concentrated and purified by rapid chromatography (silica gel, petroleum ether:ethyl acetate=10:1) to give the target compound (5g). LCMS(ESI)[M−2×tert-butyl+H]+=343.6.Step 5: Synthesis of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-formylphenyl)-1-oxopropan-2-yl) pyrrolidine-1-carboxylate (Intermediate 1-5)

[0501] A solution of tert-butyl (R)-3-((S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl) pyrrolidine-1-carboxylate (3 g, 6.6 mmol, 1 eq) in toluene (25 mL) was added to a pressure vessel, followed by adding palladium acetate (148.22 mg, 0.66 mmol, 0.1 eq), n-butyldi (1-adamantyl)phosphine (355.07 mg, 0.99 mmol, 0.15 eq) and N,N,N′,N′-tetramethylethylenediamine (1.15 g, 9.9 mmol, 1.5 eq); the mixture was stirred at 100° C. for 16 h under 2 MPa syngas (CO / H2 1:1) atmosphere. The insoluble materials were filtered off through a celite pad, the filter cake was washed with ethyl acetate, and the filtrate was concentrated. Purification by rapid chromatography (silica gel, petroleum ether:ethyl acetate=5:1) was performed to give the target compound (3g). LCMS(ESI)[M-Boc]+=303.8. 1HNMR (400 MHZ, CDCl3) δ 9.99 (s, 1H), 7.72 (dd, J=8.6, 4.5 Hz, 2H), 7.44 (dd, J=8.5, 4.4 Hz, 2H), 3.66 (dd, J=10.3, 7.7 Hz, 1H), 3.50 (t, J-8.6 Hz, 1H), 3.26 (td, J=10.4, 6.9 Hz, 1H), 3.06-2.83 (m, 3H), 2.56-2.48 (m, 1H), 2.40 (dd, J=16.5, 7.1 Hz, 1H), 2.01-1.90 (m, 1H), 1.68 (dt, J=22.3, 10.2 Hz, 1H), 1.47 (s, 9H), 1.26 (s, 5H).Synthesis of di-tert-butyl 3,3′-((2S,2'S)-((azanediylbis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R)-bis(pyrrolidine-1-carboxylate) (Intermediate 1-6)

[0502] Tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (1.6 g, 3.97 mmol, 1 eq) was dissolved in tetrahydrofuran (10 mL), ammonia methanol solution (0.62 mL, 4.36 mmol, 1.1 eq, 7 N) was added, and the mixture was stirred at room temperature for 0.5 h. Then sodium cyanoborohydride (0.49 g, 7.9.3 mmol, 2 eq) was added and the mixture was stirred at room temperature for 16 h. Liquid chromatography-mass spectrometry (LCMS) showed that the reaction was completed, and the reaction solution was directly concentrated and purified by rapid chromatography (silica gel, dichloromethane:methanol=30:1) to give the target compound (400 mg). LCMS(ESI)[M+H]+=793.3.Preparation of Intermediate 2Step 1: Synthesis of methyl benzofuran-5-carboxylate

[0503] In an autoclave, 5-bromobenzofuran (20.00 g, 101.51 mmol, 1 eq), palladium acetate (2.28 g, 10.15 mmol, 0.1 eq) and triethylamine (2.05 g, 203.02 mmol, 2 eq) were added to a mixed solvent of dimethyl sulfoxide (100 mL) and methanol (100 mL), CO gas was introduced until the pressure reached 20 atmospheres, the oil bath was heated to 80° C., and the reaction was carried out for 18 h. Water was added into the reaction. The mixture was extracted with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated, and separated through a normal phase separation column (petroleum ether:ethyl acetate=10:1) to give the target compound (6.00 g). 1HNMR (400 MHZ, CD3OD) δ 8.35 (d, J=1.6 Hz, 1H), 8.01 (dd, J=8.8, 1.6 Hz, 1H), 7.87 (d, J=2.4 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.00-6.89 (m, 1H), 3.94 (s, 3H).Step 2: Synthesis of methyl 2,3-dibromo-2,3-dihydrobenzofuran-5-carboxylate

[0504] Methyl benzofuran-5-carboxylate (6.00 g, 34.06 mmol, 1 eq) was added in anhydrous dichloromethane (60 mL) and then bromine (6.53 g, 40.87 mmol, 1.2 eq) was added slowly dropwise at 0° C. under nitrogen protection for 2 h. The reaction mixture was added slowly dropwise to a solution of sodium sulfite, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give the crude target compound (11.44 g, crude). The crude compound was used directly in the next step without further purification. 1HNMR (400 MHZ, CD3OD) δ 8.14 (s, 1H), 8.00 (dd, J-8.4, 1.6 Hz, 1H), 7.15 (s, 1H), 7.06 (d, J=8.4 Hz, 1H), 5.97 (s, 1H), 3.82 (d, J-3.6 Hz, 3H).Step 3: Synthesis of 3-bromobenzofuran-5-carboxylic acid

[0505] Methyl 2,3-dibromo-2,3-dihydrobenzofuran-5-carboxylate (11.00 g, 32.74 mmol, 1 eq) was dissolved in ethanol, an ethanol solution of potassium hydroxide (2.0 eq, 15%) was added, and the reaction was carried out at 80° C. for 2 h. The pH of the reaction mixture was adjusted to 2-3 with hydrochloric acid (2M) solution. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the target compound (10.00 g, crude). The crude compound was used directly in the next step without further purification.Step 4: Synthesis of (3-bromobenzofuran-5-yl)methanol

[0506] 3-bromobenzofuran-5-carboxylic acid (10.00 g, 41.49 mmol, 1.0 eq) was dissolved in tetrahydrofuran, and a solution of borane / tetrahydrofuran (860 mg, 62.23 mmol, 1.5 eq) was added at 0° C. and the reaction was carried out at 0° C. for 2 h. Methanol was added dropwise at low temperature to quench the reaction, and the mixture was concentrated to give the target compound (10.00 g, crude). The crude compound was used directly in the next step without further purification. LCMS(ESI)[M-OH]+=209.2.Step 5: Synthesis of 3-bromo-5-(bromomethyl)benzofuran

[0507] (3-bromobenzofuran-5-yl)methanol (10.00 g, 37.44 mmol, 1 eq) was dissolved in dichloromethane (100 mL), and phosphorus tribromide (11.15 g, 41.18 mmol, 1.1 eq) was slowly added dropwise at 0° C., and the reaction was carried out at 0° C. for 2 h. The reaction mixture was slowly poured into water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered and concentrated to give the crude target compound (10.10 g). The crude compound was used directly in the next step without further purification.Step 6: Synthesis of tert-butyl (R)-3-((S)-1-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(3-bromobenzofuran-5-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0508] Tert-butyl (R)-3-(2-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl) pyrrolidine-1-carboxylate (10.25 g, 26.38 mmol, 1 eq) was dissolved in tetrahydrofuran (100 mL), and lithium bis(trimethylsilyl)amide (5.30 g, 31.65 mmol, 1.2 eq) was slowly added dropwise at −78° C. The reaction was carried out for 1 h. 3-bromo-5-(bromomethyl)benzofuran (9.00 g, 26.38 mmol, 1 eq) was dissolved in tetrahydrofuran (30 mL) and slowly added dropwise to the reaction mixture. The reaction mixture was slowly warmed to room temperature and stirred for 12 h. The reaction mixture was added to saturated ammonium chloride, extracted with ethyl acetate, and the organic phases were combined. The mixture was washed with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated to give the target compound (12.00 g). The crude compound was used directly in the next step without further purification. LCMS(ESI)[M+Na]+=619.0.Step 7: Synthesis of(S)-3-(3-bromobenzofuran-5-yl)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)propanoic acid

[0509] Tert-butyl (R)-3-((S)-1-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(3-bromobenzofuran-5-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (11.00 g, 18.41 mmol, 1 eq) was dissolved in tetrahydrofuran (300 mL), lithium hydroxide (440 mg, 18.41 mmol, 1 eq) was dissolved in water (100 mL) and hydrogen peroxide (11 mL). The above were added to the reaction mixture at 0° C., and the reaction was carried out at room temperature for 2 h. The reaction was quenched with sodium sulfite solution, extracted with ethyl acetate, washed with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated to give the target compound (5.50 g). The crude compound was used directly in the next step without further purification. LCMS(ESI)[M-Boc+H]+=339.0.Step 8: Synthesis of tert-butyl (R)-3-((S)-3-(3-bromobenzofuran-5-yl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0510] (S)-3-(3-bromobenzofuran-5-yl)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)propanoic acid (5.50 g, 12.55 mmol, 1.0 eq) and tert-butyl N,N′-diisopropylcarbamimidate (7.54 g, 37.64 mmol, 3.0 eq) were dissolved in 2-methyltetrahydrofuran (50 mL) and heated to 80° C. for 3 h. The reaction mixture was extracted with ethyl acetate and water, the organic phase was washed with saturated brine, dried over sodium sulfate, concentrated, mixed, and purified by column chromatography to give the target compound (2.50 g). LCMS(ESI)[M+Na]+=516.2, 518.2.Step 9: Synthesis of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-formylbenzofuran-5-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0511] In a high-pressure reaction vessel, tert-butyl (R)-3-((S)-3-(3-bromobenzofuran-5-yl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (1.5 g, 3.03 mmol, 1.0 eq), palladium acetate (68 mg, 0.30 mmol, 0.1 eq), [2-(dimethylamino)ethyl]dimethylamine (704 mg, 6.06 mmol, 2.0 eq), and bis(adamantan-1-yl) (butyl)phosphine (217 mg, 0.61 mmol, 0.2 eq) were added in toluene (15 mL), and H2 / CO (v / v=1 / 1) was introduced until the pressure reached 1.3 MPa. The reaction was carried out at 100° C. for 18 h. The reaction mixture was extracted with ethyl acetate and water, washed with saturated sodium chloride solution, dried over sodium sulfate, and purified by normal phase separation (silica gel, petroleum ether:ethyl acetate=6:1, v / v) to give the target compound (700 mg). 1HNMR (400 MHZ, CDCl3) δ 10.09 (s, 1H), 8.18 (d, J-4.1 Hz, 1H), 7.94 (d, J-6.0 Hz, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.15 (t, J=7.2 Hz, 1H), 3.71-3.34 (m, 2H), 3.23-3.13 (m, 1H), 3.02-2.77 (m, 3H), 2.45 (d, J=8.6 Hz, 1H), 2.39-2.28 (m, 1H), 1.92-1.84 (m, 1H), 1.57 (d, J=13.9 Hz, 1H), 1.40 (s, 9H), 1.21 (s, 9H).Tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-fluoro-5-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (Intermediate 3-5)Synthesis of tert-butyl (R)-3-((S)-1-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(3-bromo-5-fluorophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (Intermediate 3-1)

[0512] The target product (21.9 g) was synthesized from 1-bromo-3-(bromomethyl)-5-fluorobenzene as the starting material by referring to the method of Intermediate 1-2. LCMS(ESI)[M-tert-butyl+H]+=521.2.Synthesis of(S)-3-(3-bromo-5-fluorophenyl)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)propanoic acid (Intermediate 3-2)

[0513] The target product (8.8 g) was synthesized by referring to the method of Intermediate 1-3. LCMS(ESI)[M-tert-butyl+H]+=359.9.Synthesis of tert-butyl (R)-3-((S)-3-(3-bromo-5-fluorophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (Intermediate 3-3)

[0514] The target product (6.1 g) was synthesized by referring to the method of Intermediate 1-4. LCMS(ESI)[M−2×tert-butyl+H]+=359.9.Synthesis of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-fluoro-5-vinylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (Intermediate 3-4)

[0515] In a three-necked flask, tert-butyl (R)-3-((S)-3-(3-bromo-5-fluorophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (5.6 g) was dissolved in 1,4-dioxane (45 mL). Potassium vinyltrifluoroborate (8 g), [1,1′-bis(diphenylphosphino) ferrocene]palladium (II) dichloride dichloromethane complex (922 mg), and triethylamine (3.6 g) were added in turn. Water (15 mL) was added. The mixture was heated to 75° C. under nitrogen protection and stirred for 5 h. LCMS showed that the reaction was completed. The insoluble materials were filtered off through diatomaceous earth, the filter cake was washed with an appropriate amount of ethyl acetate, and the filtrate was concentrated. The filtrate was separated and purified by rapid chromatography (silica gel, PE:EA=10:1, v / v) to give the target compound (4.4 g). LCMS(ESI)[M−2×tert-butyl+H]+=308.3.Synthesis of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-fluoro-5-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (Intermediate 3-5)

[0516] In a three-necked flask, tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-fluoro-5-vinylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (4.4 g, 10.53 mmol, 1 eq) was dissolved in tetrahydrofuran (44 mL) and water (12 mL). The mixture was under nitrogen protection and then potassium osmate (388 mg, 1.05 mmol, 0.1 eq) and sodium periodate (6.76 g, 31.59 mmol, 3 eq) were added in turn under ice bath. The reaction mixture was warmed to room temperature and stirred for 3 h. The insoluble materials were filtered off, the filtrate was poured into water, and then extracted with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by rapid chromatography (silica gel, PE:EA=10:1, v / v) to give the target compound (2.7 g). LCMS(ESI)[M-2×tert-butyl+H]+=310.0. 1HNMR (400 MHZ, DMSO-d6) δ 9.97 (d, J=1.5 Hz, 1H), 7.63 (s, 1H), 7.46 (d, J-9.8 Hz, 1H), 3.52 (q, J=10.5 Hz, 1H), 3.42-3.34 (m, 1H), 3.24-3.09 (m, 1H), 3.02 (t, J=10.0 Hz, 1H), 2.83 (q, J=13.9 Hz, 2H), 2.59 (d, J=8.9 Hz, 1H), 2.30 (s, 1H), 1.91-1.76 (m, 1H), 1.68-1.49 (m, 1H), 1.40 (s, 9H), 1.21 (s, 9H).Synthesis of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(5-formylpyridin-3-yl)-1-oxopropan-2-yl) pyrrolidine-1-carboxylate (Intermediate 4-1)

[0517] The target compound (320 mg) was synthesized from 3-bromo-5-(bromomethyl)pyridine instead of 1-bromo-3-(bromomethyl)benzene by referring to the method of Intermediate 1-5. LCMS(ESI)[M+H]+=405.2; 1HNMR (400 MHZ, DMSO-d6) δ 10.11 (s, 1H), 8.95 (d, J=1.8 Hz, 1H), 8.71 (d, J=1.9 Hz, 1H), 8.09 (s, 1H), 3.59-3.47 (m, 2H), 3.21-3.12 (m, 1H), 3.05 (t, J=10.0 Hz, 1H), 2.96-2.88 (m, 1H), 2.87-2.79 (m, 1H), 2.65-2.56 (m, 1H), 2.39-2.27 (m, 1H), 1.90-1.81 (m, 1H), 1.64-1.54 (m, 1H), 1.40 (s, 9H), 1.19 (s, 9H).Example 1 (Compound 5)Preparation of (2S,2'S)-3,3′-(((((S)-5-amino-5-carboxypentyl) azanediyl)bis(methylene))bis(5-fluoro-3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)Step 1: Synthesis of N6,N6-bis(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-5-fluorobenzyl)-N2-(tert-butoxycarbonyl)-L-lysine

[0518] Tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-fluoro-5-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (376 mg, 0.893 mmol, 2.2 eq) and (tert-butoxycarbonyl)-L-lysine (100 mg, 0.406 mmol, 1.0 eq) were dissolved in tetrahydrofuran (2 mL), and sodium cyanoborohydride (64 mg, 1.02 mmol, 2.5 eq) and a drop of acetic acid were added. The reaction mixture was stirred at room temperature overnight. A saturated ammonium chloride solution and dichloromethane were added. The organic solvent was evaporated under reduced pressure and the residue was purified by rapid chromatography (Silica gel, DCM:MeOH=15:1, volume ratio) to obtain the target compound (89 mg). LCMS(ESI)[M+H]+=1057.9.Step 2: Synthesis of (2S,2'S)-3,3′-(((((S)-5-amino-5-carboxypentyl) azanediyl)bis(methylene))bis(5-fluoro-3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)

[0519] N6,N6-bis(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-5-fluorobenzyl)-N2-(tert-butoxycarbonyl)-L-lysine (89 mg, 0.084 mmol, 1.0 eq) was dissolved in 1,4-dioxane (0.2 mL), and a solution of 4 M HCl (1,4-dioxane) (0.2 mL) was added. The reaction mixture was stirred at room temperature overnight. LCMS monitoring showed that the reaction was complete. The solvent was evaporated under reduced pressure, and the residue was purified by preparative-HPLC (C18, 10 mmol / L NH4HCO3 in water / acetonitrile) to obtain the target compound (9.8 mg). LCMS(ESI)[M+H]+=645.4; 1HNMR (400 MHZ, D2O) 8 6.97-6.86 (m, 6H), 3.78 (s, 4H), 3.64-3.57 (m, 1H), 3.51-3.42 (m, 2H), 3.40-3.31 (m, 2H), 3.23-3.13 (m, 2H), 2.97-2.87 (m, 2H), 2.77-2.68 (m, 4H), 2.66-2.53 (m, 2H), 2.45-2.33 (m, 4H), 2.10-2.00 (m, 2H), 1.81-1.53 (m, 6H), 1.32-1.17 (m, 2H).Example 2 (Compound 6)Preparation of (2S,2'S)-3,3′-(((((5-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzofuran-3-yl)methyl)azanediyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)

[0520] Step 1: Synthesis of di-tert-butyl 3,3′-((2S,2'S)-(((((5-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzofuran-3-yl)methyl)azanediyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R)-bis(pyrrolidine-1-carboxylate)

[0521] Di-tert-butyl 3,3′-((2S,2'S)-((azanediylbis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R)-bis(pyrrolidine-1-carboxylate) (50 mg, 0.063 mmol, 1.0 eq) and tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-formylbenzofuran-5-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (33 mg, 0.076 mmol, 1.2 eq) were dissolved in tetrahydrofuran (0.2 mL), and sodium cyanoborohydride (6 mg, 0.095 mmol, 1.5 eq) and one drop of acetic acid were added. The reaction mixture was stirred at room temperature overnight. A saturated ammonium chloride solution and dichloromethane were added. The organic phase was concentrated under reduced pressure and purified by rapid chromatography (Silica gel, DCM:MeOH=15:1, volume ratio) to obtain the target compound (45 mg).

[0522] Step 2: Synthesis of (2S,2'S)-3,3′-(((((5-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzofuran-3-yl)methyl)azanediyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid) Di-tert-butyl 3,3′-((2S,2'S)-(((((5-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzofuran-3-yl)methyl)azanediyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R)-bis(pyrrolidine-1-carboxylate) (45 mg, 0.037 mmol, 1.0 eq) was dissolved in 1,4-dioxane (0.2 mL), 4 M HCl (1,4-dioxane) solution (0.2 mL) was added, and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by preparative-HPLC (C18, water / acetonitrile solution of 10 mmol / L NH4HCO3) to obtain the target compound (13 mg). LCMS(ESI)[M+H]+=751.5, 1HNMR (400 MHZ, D2O) δ 7.45 (s, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.18 (t, J-7.5 Hz, 2H), 7.06 (d, J=9.1 Hz, 4H), 7.01 (d, J=11.7 Hz, 4H), 3.53-3.44 (m, 3H), 3.32-3.18 (m, 7H), 3.12-3.05 (m, 3H), 2.83-2.67 (m, 7H), 2.65-2.54 (m, 3H), 2.38-2.27 (m, 7H), 2.03-1.96 (m, 3H), 1.68-1.60 (m, 3H).Example 3 (Compound 12)Preparation of (2S,2'S)-3,3′-((((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-5-fluorobenzoyl)azanediyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)Step 1: Synthesis of 3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-5-fluorobenzoic acid

[0523] Tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-fluoro-5-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (50 mg), sodium hydroxide (8 mg) and potassium permanganate (30 mg) were dissolved in acetonitrile (0.5 mL) and water (0.5 mL). The reaction mixture was stirred at 60° C. overnight. Water and dichloromethane were added. The organic phase was concentrated under reduced pressure and purified by rapid chromatography (Silica gel, DCM:MeOH=30:1, volume ratio) to obtain the target compound (15 mg). LCMS(ESI)[M-Boc+H]+=338.49.

[0524] Step 2: Synthesis of di-tert-butyl 3,3′-((2S,2'S)-((((3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-5-fluorobenzoyl)azanediyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R)-bis(pyrrolidine-1-carboxylate) 3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-5-fluorobenzoic acid (15 mg) was dissolved in N,N-dimethylformamide (0.3 mL), and di-tert-butyl 3,3′-((2S,2'S)-((azanediylbis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R)-bis(pyrrolidine-1-carboxylate) (27 mg), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (15 mg), and N,N-diisopropylethylamine (14 mg) were added. The reaction mixture was stirred at room temperature overnight. Water and ethyl acetate were added. The organic phase was concentrated under reduced pressure and purified by rapid chromatography (Silica gel, DCM: MeOH=30:1, volume ratio) to obtain the target compound (20 mg). LCMS(ESI)[M-Boc+H]+=1111.92.Step 3: Synthesis of (2S,2'S)-3,3′-((((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-5-fluorobenzoyl)azanediyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)

[0525] Di-tert-butyl 3,3′-((2S,2'S)-((((3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-5-fluorobenzoyl)azanediyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R)-bis(pyrrolidine-1-carboxylate) (115 mg) was dissolved in 1,4-dioxane (0.2 mL), 4 M HCl (1,4-dioxane) solution (0.2 mL) was added, and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and purified by preparative-HPLC (C18, 10 mmol / L NH4HCO3 in water / acetonitrile) to obtain the target compound (39.9 mg). LCMS(ESI)[M+H]+=743.65; 1HNMR (400 MHZ, D2O) δ 7.30-7.18 (m, 2H), 7.16-6.93 (m, 7H), 6.92-6.81 (m, 2H), 4.60 (s, 2H), 4.41 (s, 2H), 3.42-3.23 (m, 6H), 3.20-3.06 (m, 3H), 2.88-2.60 (m, 9H), 2.45-2.24 (m, 6H), 2.11-1.93 (m, 3H), 1.75-1.53 (m, 3H).Example 4 (Compound 47)Preparation of (2S,2'S,2″S)-3,3′,3″-((nitrilotris(methylene))tris(benzofuran-3,5-diyl))tris(2-((R)-pyrrolidin-3-yl)propanoic acid)

[0526] Step 1: Synthesis of tri-tert-butyl 3,3′,3″-((2S,2'S,2″S)-((nitrilotris(methylene))tris(benzofuran-3,5-diyl))tris(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R,3″R)-tris(pyrrolidine-1-carboxylate) Tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-formylbenzofuran-5-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (600 mg, 1.38 mmol, 1 eq) was dissolved in isopropanol (6 mL), ammonia methanol solution (1.0 eq, 7.0M) and sodium triacetoxyborohydride (436 mg, 2.10 mmol, 1.5 eq) were added, and the reaction was carried out at 25° C. for 16 h. The reaction mixture was concentrated and purified by silica gel column chromatography (Silica gel, petroleum ether / ethyl acetate=1 / 1, volume ratio) to obtain the target compound (30 mg). LCMS(ESI)[M+H]+=1322.6.Step 2: Synthesis of (2S,2'S,2″S)-3,3′,3″-((nitrilotris(methylene))tris(benzofuran-3,5-diyl))tris(2-((R)-pyrrolidin-3-yl)propanoic acid)

[0527] Tri-tert-butyl 3,3′,3″-((2S,2'S,2″S)-((nitrilotris(methylene))tris(benzofuran-3,5-diyl))tris(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R,3″R)-tris(pyrrolidine-1-carboxylate) (35 mg, 0.03 mmol, 1 eq) was dissolved in hydrogen chloride dioxane solution (1 mL, 4M) and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated, water was added, and the mixture was lyophilized to obtain the target compound (15.88 mg). LCMS(ESI)[M+H]+=831.4; 1HNMR (400 MHZ, CD3OD) δ 8.10 (s, 3H), 7.56-7.47 (m, 6H), 7.27 (d, J=8.4 Hz, 3H), 4.64 (s, 6H), 3.52-3.35 (m, 6H), 3.26-3.19 (m, 3H), 3.08-2.93 (m, 12H), 2.52 (d, J=7.6 Hz, 3H), 2.16 (d, J=7.2 Hz, 3H), 1.91-1.73 (m, 3H).Example 5 (Compound 89)Preparation of (2S,2'S)-3,3′-((((3-fluoro-5-methoxyphenethyl) azanediyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)Step 1: Synthesis of (E)-1-(2-ethoxyvinyl)-3-fluoro-5-methoxybenzene

[0528] Under nitrogen, in a three-necked flask, [1,1′-bis(diphenylphosphino) ferrocene]palladium (II) dichloride dichloromethane complex (1.14 g), cesium carbonate (29.32 g), 1,4-dioxane (180 mL), and water (30 mL) were added. 1-bromo-3-fluoro-5-methoxybenzene (6.15 g) and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.54 g) were added in turn; the reaction mixture was heated to 100° C. and reacted for 3 h. After the reaction was completed, the reaction mixture was quenched with saturated saline solution and extracted with ethyl acetate. After combining the organic phases, the organic phase was washed with saturated saline solution, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (Silica gel, petroleum ether:ethyl acetate=3:1, volume ratio) to obtain the target compound (3.60 g).Step 2: Synthesis of 2-(3-fluoro-5-methoxyphenyl) acetaldehyde

[0529] (E)-1-(2-ethoxyvinyl)-3-fluoro-5-methoxybenzene (500 mg) was dissolved in HCl / dioxane (5 mL) and the mixture was stirred at room temperature for 16 h. LCMS showed that the reaction was completed. The reaction mixture was concentrated directly and purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate=10:1, volume ratio) to obtain the target compound (150 mg). LCMS(ESI)[M+H]+=169.07.Step 3: Synthesis of di-tert-butyl 3,3′-((2S,2'S)-((((3-fluoro-5-methoxyphenethyl) azanediyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R)-bis(pyrrolidine-1-carboxylate)

[0530] 2-(3-fluoro-5-methoxyphenyl) acetaldehyde (47 mg) was dissolved in methanol (5 mL), and di-tert-butyl 3,3′-((2S,2'S)-((azanediylbis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R)-bis(pyrrolidine-1-carboxylate) (200 mg) and two drops of acetic acid were added at room temperature. The mixture was stirred at room temperature for 16 h. The reaction mixture was directly concentrated and purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate=5:1, volume ratio) to obtain the target compound (120 mg). LCMS(ESI)[M+H]+=944.89.Step 4: Synthesis of (2S,2'S)-3,3′-((((3-fluoro-5-methoxyphenethyl) azanediyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)

[0531] Di-tert-butyl 3,3′-((2S,2'S)-((((3-fluoro-5-methoxyphenethyl) azanediyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R)-bis(pyrrolidine-1-carboxylate) (120 mg) was dissolved in HCl / dioxane (5 mL) and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated directly and separated and purified by preparative-HPLC (C18, 0.1% FA in water / acetonitrile) to obtain the target compound (47.46 mg). LCMS(ESI)[M+H]+=632.4.Example 6 (Compound 62)Preparation of (2S,2'S)-3,3′-((((3-fluoro-5-methoxybenzyl) azanediyl)bis(ethane-2,1-diyl))bis(1H-indole-1,6-diyl))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)

[0532] Step 1: Synthesis of 2,2′-((3-fluoro-5-methoxybenzyl) azanediyl)bis(ethan-1-ol) 2,2′-azanediylbis(ethan-1-ol) (2.00 g) was added in dichloromethane (30 mL), and 3-fluoro-5-methoxybenzaldehyde (4.00 g) and sodium triacetoxyborohydride (12.00 g) were added at 25° C. The reaction was carried out at 25° C. for 2 h, and the reaction was monitored by LCMS. The reaction mixture was extracted with dichloromethane and water. After the organic phases were concentrated under reduced pressure, the residue was purified (by reversed-phase column chromatography: acetonitrile / water=10%) to obtain the target compound (4.00 g). LCMS(ESI)[M+H]+=244.2.

[0533] Step 2: Synthesis of 2-chloro-N-(2-chloroethyl)-N-(3-fluoro-5-methoxybenzyl) ethan-1-amine 2,2′-((3-fluoro-5-methoxybenzyl) azanediyl)bis(ethan-1-ol) (1.50 g) was added to thionyl chloride (15 mL) and the reaction was carried out at 70° C. overnight. Compounds were detected by LCMS. The thionyl chloride was concentrated under reduced pressure. The residue was triturated with ethyl acetate. The mixture was extracted with aqueous ammonium chloride solution without further purification to obtain the target compound (1.8 g, crude product) which was used in the next step without further purification.Step 3: Synthesis of di-tert-butyl 3,3′-((2S,2'S)-((((3-fluoro-5-methoxybenzyl) azanediyl)bis(ethane-2,1-diyl))bis(1H-indole-1,6-diyl))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R)-bis(pyrrolidine-1-carboxylate)

[0534] Tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(1H-indol-6-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (0.5 g) was added in N,N-dimethylformamide (5 mL) and 2-chloro-N-(2-chloroethyl)-N-(3-fluoro-5-methoxybenzyl) ethan-1-amine (338 mg) and cesium carbonate (1.2 g) were added at room temperature. The reaction mixture was stirred at 100° C. under nitrogen overnight. After the reaction mixture was detected by LCMS, saturated saline solution was added. The reaction mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After the organic phases were concentrated under reduced pressure, the residue was washed by silica gel column chromatography (pure ethyl acetate) to obtain the target compound (190 mg). LCMS(ESI)[M+H]+=1036.6.Step 4: Synthesis of (2S,2'S)-3,3′-((((3-fluoro-5-methoxybenzyl) azanediyl)bis(ethane-2,1-diyl))bis(1H-indole-1,6-diyl))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)

[0535] Di-tert-butyl 3,3′-((2S,2'S)-((((3-fluoro-5-methoxybenzyl) azanediyl)bis(ethane-2,1-diyl))bis(1H-indole-1,6-diyl))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R)-bis(pyrrolidine-1-carboxylate) (140 mg) was added in TFA (2 mL) and the mixture was stirred at 25° C. for 0.5 h. LCMS detected the desired product. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in acetonitrile and purified by preparative-HPLC (FA) to obtain the target compound (13.6 mg). LCMS(ESI)[M+H]+=725.04; 1HNMR (400 MHZ, MeOD-d4) δ 8.42 (s, 1H), 7.42 (d, J-8.0 Hz, 2H), 7.11 (d, J=3.2 Hz, 2H), 6.91 (d, J=7.2 Hz, 2H), 6.87-6.84 (m, 2H), 6.45-6.43 (m, 3H), 6.29 (t, J=2.8 Hz, 2H), 4.07 (d, J-6.2 Hz, 4H), 3.63 (d, J=3.2 Hz, 3H), 3.59 (s, 2H), 3.21-3.18 (m, 4H), 3.13-3.03 (m, 6H), 2.99-2.92 (m, 2H), 2.87 (s, 2H), 2.78-2.66 (m, 2H), 2.60-2.54 (m, 2H), 2.38-2.30 (m, 2H), 2.01 (d, J=24.0 Hz, 2H), 1.85-1.76 (m, 1H), 1.56 (s, 1H).Example 7 (Compound 95)Preparation of (2S,2'S)-3,3′-((((2-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenoxy)acetyl)azanediyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)Step 1: Synthesis of (3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl) boronic acid

[0536] Tert-butyl (R)-3-((S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (1.9 g, 4.18 mmol, 1 eq), (dihydroxyboranyl) boronic acid (562.29 mg, 6.27 mmol, 1.5 eq), potassium acetate (1230.7 mg, 12.54 mmol, 3 eq), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-1-propyl-1,1′-biphenyl (199.27 mg, 0.42 mmol, 0.1 eq) and X-Phos Pd G2 (164 mg, 0.21 mmol, 0.05 eq) were added to EtOH (20 mL). The reaction mixture was purged with nitrogen three times, and reacted at 90° C. for 16 h; The product was detected by LCMS, ethyl acetate (20 mL) was added to the reaction system. The mixture was filtered through diatomaceous earth, and the filtrate was evaporated under reduced pressure to obtain the target compound (2.0 g). The crude product was not further purified and directly used for the next step. LCMS [M−2×tert-butyl+H]+=308.2.Step 2: Synthesis of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-hydroxyphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0537] (3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl) boronic acid (2000 mg, 4.77 mmol, 1 eq) was dissolved in THF (20 mL), and hydrogen peroxide (8 mL, 235.2 mmol, 49.31 eq) wad added, and the reaction mixture was stirred at 20° C. for 16 h. LCMS showed the desired product. A saturated solution of sodium bisulfite (20 mL) and ethyl acetate (20 mL) were added, and the mixture was extracted. The organic phase was dried over sodium sulfate, concentrated, and purified by rapid chromatography (Silica gel, PE: EtOAc=4:1, v / v) to obtain the target compound (800 mg). LCMS(ESI)[M+H]+=392.2.Step 3: Synthesis of tert-butyl (R)-3-((S)-3-(3-(2-(benzyloxy)-2-oxoethoxy)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0538] Tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-hydroxyphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (2.0 g, 5.11 mmol, 1 eq), benzyl 2-bromoacetate (2.34 g, 10.22 mmol, 2 eq) and potassium carbonate (2.12 g, 15.33 mmol, 3 eq) were added to acetonitrile (50 mL), and the mixture was reacted at 90° C. for 16 h; LCMS showed the desired product. Rapid chromatography (Silica gel, PE: EtOAc=5:1, volume ratio) was used to obtain the target compound (2.5 g). LCMS(ESI)[M+Na]+=561.9.Step 4: Synthesis of 2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenoxy) acetic acid

[0539] Tert-butyl (R)-3-((S)-3-(3-(2-(benzyloxy)-2-oxoethoxy)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl) pyrrolidine-1-carboxylate (2.5 g, 4.63 mmol, 1 eq) was dissolved in methanol (50 mL), followed by adding Pd / C (300 mg, 10%), and the mixture was purged with hydrogen for three times. The reaction mixture was stirred at room temperature for 16 h. LCMS showed the reaction was completed. The mixture was filtered, and the filtrate was concentrated to obtain the target compound (1.5 g). LCMS(ESI)[M+Na]+=472.2.

[0540] Step 5: Synthesis of di-tert-butyl 3,3′-((2S,2'S)-((((2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenoxy)acetyl)azanediyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R)-bis(pyrrolidine-1-carboxylate) Di-tert-butyl 3,3′-((2S,2'S)-((azanediylbis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R)-bis(pyrrolidine-1-carboxylate) (88.1 mg, 0.11 mmol, 1 eq), 2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenoxy) acetic acid (50 mg, 0.11 mmol, 1 eq), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (41.83 mg, 0.11 mmol, 1 eq) and N,N-diisopropylethylamine (43.12 mg, 0.33 mmol, 3 eq) were dissolved in N,N-dimethylformamide (3 mL); the mixture was stirred at room temperature for 16 h, and LCMS showed that the reaction was completed; the reaction solvent was evaporated, and the residue was purified by thin-layer silica gel plate (DCM:MeOH=20:1, volume ratio) to obtain the target compound (100 mg). LCMS(ESI)[M+Na]+=1245.8.Step 6: Synthesis of (2S,2'S)-3,3′-((((2-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenoxy)acetyl)azanediyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)

[0541] Di-tert-butyl 3,3′-((2S,2'S)-((((2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenoxy)acetyl)azanediyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R)-bis(pyrrolidine-1-carboxylate) (100 mg, 0.08 mmol, 1 eq) was added to hydrochloric acid-dioxane (2 mL, 4.0M) and reacted at room temperature for 6 h. The reaction mixture was filtered and the filter cake was washed with dioxane to obtain the target compound (46 mg). LCMS(ESI)[M+H]+=755.2. 1HNMR (400 MHZ, CD3OD) δ 7.34-7.20 (m, 5H), 7.18-7.10 (m, 4H), 6.92-6.85 (m, 2H), 6.7-6.75 (m, 1H), 4.92 (s, 2H), 4.61 (s, 4H), 3.57-3.40 (m, 6H), 3.34-3.21 (m, 3H), 2.99-2.81 (m, 11H), 2.78-2.72 (m, 3H), 2.56-2.49 (m, 3H), 2.29-2.15 (m, 3H), 1.87-1.81 (m, 3H).Example 8 (Compound 96)

[0542] Preparation of(S)-3-(3-(2-((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)(2-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenoxy)ethyl)amino)-2-oxoethyl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acidStep 1: Preparation of tert-butyl (R)-3-((S)-1-(tert-butoxy)-1-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)pyrrolidine-1-carboxylate

[0543] Tert-butyl (R)-3-((S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (1.5 g, 3.30 mmol, 1.0 eq) was dissolved in 1,4-dioxane (20 mL) in a single-necked flask, followed by adding [1,1′-bis(diphenylphosphino) ferrocene]palladium (II) dichloride dichloromethane complex (270.0 mg, 0.33 mmol, 0.1 eq), bis(pinacolato)diboron (1.26 g, 4.95 mmol, 1.5 eq) and potassium acetate (972 mg, 9.9 mmol, 3 eq); the mixture was stirred at 90° C. for 16 h under nitrogen. LCMS detection showed that the reaction was completed, and the reaction mixture was directly concentrated, separated and purified by rapid chromatography (Silica gel, PE: EtOAc-2:1) to obtain the target compound (1.2 g). LCMS(ESI)[M-Boc+H]+=402.2.Step 2: Preparation of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-hydroxyphenyl)-1-oxopropan-2-yl) pyrrolidine-1-carboxylate

[0544] In a single-neck bottle, the product from the first step (1.2 g, 2.39 mmol, 1.0 eq) was dissolved in tetrahydrofuran (20 mL). Subsequently hydrogen peroxide (0.5 mL) was added, and the mixture was stirred at room temperature for 16 h. LCMS detection showed that the reaction was completed, and the reaction mixture was directly concentrated, separated and purified by rapid chromatography (Silica gel, PE: EtOAc=1:1) to obtain the target compound (800.0 mg). LCMS(ESI)[M−2×tert-butyl+H]+=280.0.Step 3: Preparation of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-(2-(1,3-dioxoisoindolin-2-yl) ethoxy)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0545] In a single-neck bottle, the product from the second step (500.0 mg, 1.28 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (5 mL), followed by adding 2-(2-bromoethyl) isoindoline-1,3-dione (647.7 mg, 2.56 mmol, 2 eq), potassium carbonate (530.7 mg, 3.83 mmol, 3 eq). The mixture was stirred at 90° C. for 2 h. LCMS detection showed that the reaction was completed, and the reaction mixture was directly concentrated, separated and purified by rapid chromatography (Silica gel, PE: EtOAc=1:1) to obtain the target compound (280 mg). LCMS(ESI)[M+H]+=565.3.Step 4: Preparation of tert-butyl (R)-3-((S)-3-(3-(2-aminoethoxy)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0546] In a single-neck bottle, the product from the third step (280.0 mg, 0.5 mmol, 1.0 eq) was dissolved in ethanol (10 mL), followed by adding hydrazine hydrate (124 mg, 2.50 mmol, 5.0 eq). The mixture was reacted at 90° C. for 16 h. LCMS detection showed that the reaction was completed, and the reaction mixture was directly concentrated, separated and purified by rapid chromatography (Silica gel, PE: EtOAc=1:5) to obtain the target compound (160 mg). LCMS(ESI)[M+H]+=435.3.Step 5: Preparation of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-(((2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenoxy)ethyl)amino)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0547] In a single-neck bottle, the product from the fourth step (160 mg, 0.37 mmol, 1.0 eq) was dissolved in methanol (10 mL). Subsequently, tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (178.1 mg, 0.44 mmol, 1.2 eq) was added, followed by addition of sodium cyanoborohydride (23.2 mg, 0.37 mmol, 1.0 eq). The mixture was stirred at room temperature for 16 h. LCMS detection showed that the reaction was completed, and the reaction mixture was directly concentrated, separated and purified by rapid chromatography (Silica gel, PE: EtOAc=1:5) to obtain the target compound (233 mg). LCMS(ESI)[M+H]+=822.6.Step 6: Preparation of tert-butyl (R)-3-((S)-3-(3-allylphenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0548] Tert-butyl (R)-3-((S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (7.0 g, 15.4 mmol, 1.0 eq) was dissolved in 1,4-dioxane (20 mL) and water (4 mL) in a single-necked flask, followed by adding 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.2 g, 30.8 mmol, 2 eq), potassium phosphate 46.2 mmol, (9.8 g, 3 eq) and [1,1′-bis(diphenylphosphino) ferrocene]palladium (II) dichloride dichloromethane complex (1.25 g, 1.54 mmol, 0.1 eq). The mixture was degassed with nitrogen for 3 times and stirred at 90° C. for 16 h. LCMS detection showed that the reaction was completed, and the reaction mixture was directly concentrated, separated and purified by rapid chromatography (Silica gel, PE: EtOAc=2:1) to obtain the target compound (5.0 g). LCMS [M−2×tert-butyl+H]+=304.1.Step 7: Preparation of 2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl) acetic acid

[0549] In a single-neck bottle, the product from the sixth step (6.0 g, 14.4 mmol, 1.0 eq) was dissolved in 1,4-dioxane (100 mL), followed by adding sodium periodate (12.3 g, 57.75 mmol, 4 eq) and potassium osmate dihydrate (532.0 mg, 1.44 mmol, 0.1 eq). The mixture was stirred at room temperature for 16 h. LCMS detection showed that the reaction was completed, and the reaction mixture was directly concentrated, separated and purified by rapid chromatography (Silica gel, PE: EtOAc=1:1) to obtain the target compound (500 mg). LCMS(ESI)[M+H]+=434.2.Step 8: Preparation of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-((N-(2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenoxy)ethyl)-2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl) acetamido)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0550] In a single-neck bottle, the product from the fifth step (70 mg, 0.0852 mmol, 1.0 eq) was dissolved in DMF (5 mL), followed by adding the product obtained in the seventh step (44.3 mg, 0.102 mmol, 1.2 eq), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (64.7 mg, 0.17 mmol, 2.0 eq) and N,N-diisopropylethylamine (33.0 mg, 0.25 mmol, 3.0 eq). The mixture was stirred at room temperature for 16 h, and LCMS showed the reaction was complete. The reaction mixture was directly concentrated, separated and purified by rapid chromatography (Silica gel, PE: EtOAc=1:8) to obtain the target compound (70 mg). LCMS(ESI)[M+H]+=1237.9.Step 9: Preparation of(S)-3-(3-(2-((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)(2-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenoxy)ethyl)amino)-2-oxoethyl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid

[0551] In a single-neck bottle, the product from the eighth step (70.0 mg, 0.056 mmol) was dissolved in hydrochloric acid-dioxane (2 mL), and stirred at room temperature for 16 h. LCMS showed the reaction was completed. The reaction mixture was directly concentrated, separated and purified by preparative chromatography to obtain the target compound (27.2 mg). LCMS(ESI)[M+H]+=769.4. 1HNMR (400 MHZ, D2O) δ 7.20 (dq, J-30.0, 7.5 Hz, 3H), 7.11-6.86 (m, 6H), 6.81 (s, 1H), 6.69-6.59 (m, 2H), 4.59 (d, J-4.6 Hz, 2H), 4.10 (t, J=5.0 Hz, 1H), 4.00 (d, J=5.2 Hz, 1H), 3.88 (s, 1H), 3.79 (d, J=5.2 Hz, 1H), 3.69 (d, J=5.2 Hz, 2H), 3.29 (dtt, J=13.1, 9.3, 4.6 Hz, 6H), 3.12 (dd, J=11.9, 7.9 Hz, 3H), 2.87-2.58 (m, 8H), 2.54-2.48 (m, 1H), 2.41-2.23 (m, 6H), 2.01 (s, 3H), 1.63 (dt, J=22.4, 11.3 Hz, 3H).Example 9 (Compound 8)Preparation of 3,3′-(((((4-(2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzofuran-2-yl)methyl)azanediyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)Step 1: Synthesis of methyl 3-hydroxy-2-iodobenzoate

[0552] Methyl 2-amino-3-hydroxybenzoate (25 g, 149.65 mmol, 1 eq) was dissolved in an aqueous solution of sulfuric acid (1000 mL, 1.0M) and cooled to 0° C. An aqueous solution (100 mL) of sodium nitrite (11.25 g, 163.0 mmol, 1.08 eq) was added and the mixture was stirred at 25° C. for 20 min. An aqueous solution (100 mL) of potassium iodide (111.7 g, 672.9 mmol, 4.5 eq) was added and the mixture was stirred at 70° C. for 1.5 h. LCMS detection showed that the reaction was completed. Water and ethyl acetate was added to the reaction mixture, and the mixture was extracted. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated and purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate=5:1) to obtain the target compound (20.0 g). LCMS(ESI)[M+H]+=278.9.Step 2: Synthesis of methyl 2-(hydroxymethyl)benzofuran-4-carboxylate

[0553] The product obtained in the first step (20.0 g, 71.94 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (200 mL), followed by adding cuprous iodide (1.37 g, 7.19 mmol, 0.1 eq), bis(triphenylphosphine) palladium (II) dichloride (5 g, 7.19 mmol, 0.1 eq), triethylamine (21.86 g, 214.55 mmol, 3.0 eq), and propargyl alcohol (6.1 g, 108.81 mmol, 1.5 eq). The reaction mixture was stirred at 75° C. for 16 h under nitrogen. LCMS detection showed that the reaction was completed. Water and ethyl acetate were added to the reaction mixture and the mixture was extracted. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated and purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate=10:1) to obtain the target compound (11g). LCMS(ESI)[M+H]+=207.4.Step 3: Synthesis of methyl 2-(((tert-butyldiphenylsilyl)oxy)methyl)benzofuran-4-carboxylate

[0554] The product obtained in the second step (11.0 g, 53.38 mmol, 1.0 eq) was dissolved in dichloromethane (80 mL), followed by adding imidazole (4.5 g, 66.09 mmol, 1.5 eq) and tert-butyl (chloro)diphenylsilane (13.0 g, 47.30 mmol, 0.8 eq); the mixture was stirred at 25° C. for 16 h. LCMS detection showed that the reaction was completed. The reaction mixture was filtered, and the filtrate was directly evaporated under reduced pressure. The residue was separated and purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate=10:1) to obtain the target compound (12.2 g). LCMS(ESI)[M+Na]+=467.4.Step 4: Synthesis of (2-(((tert-butyldiphenylsilyl)oxy)methyl)benzofuran-4-yl)methanol

[0555] The product obtained in the third step (12.2 g, 27.47 mmol, 1 eq) was dissolved in tetrahydrofuran (100 mL), lithium borohydride (1.79 g, 82.41 mmol, 3.0 eq) was added at 0° C., and the mixture was stirred at 25° C. for 16 h. LCMS detection showed that the reaction was completed. Water and ethyl acetate were added, and the mixture was extracted. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated and mixed. The residue was separated and purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate=2:1) to obtain the target compound (7.64 g). LCMS(ESI)[M+Na]+=439.4.Step 5: Synthesis of ((4-(bromomethyl)benzofuran-2-yl)methoxy) (tert-butyl)diphenylsilane

[0556] The product of the fourth step (2.0 g, 4.81 mmol, 1.0 eq) was added to dichloromethane (20 mL), phosphorus tribromide (1.95 g, 7.21 mmol, 1.5 eq) was added at 0° C., and the mixture was stirred for 2 h. TLC detection showed that the reaction was completed. Saturated ammonium chloride aqueous solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was separated and purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate=100:1) to obtain the target compound (1.42 g).

[0557] Step 6: Synthesis of tert-butyl (R)-3-(2-(tert-butoxy)-2-oxoethyl) pyrrolidine-1-carboxylate (R)-2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl) acetic acid (25.0 g, 109.11 mmol, 1.0 eq) was dissolved in dichloromethane (200 mL), N,N′-dicyclohexylcarbodiimide (22.5 g, 109.11 mmol, 1.0 eq), tert-butanol (24.25 mL, 327.33 mmol, 3.0 eq) and 4-dimethylaminopyridine (13.3 g, 109.11 mmol, 1.0 eq) were added at 25° C., and the mixture was stirred for 16 h after the addition. LCMS detection showed that the reaction was completed. Water and ethyl acetate were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated and purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate=10:1) to obtain the target compound (24.0 g).

[0558] Step 7: Synthesis of tert-butyl (3R)-3-(1-(tert-butoxy)-3-(2-(((tert-butyldiphenylsilyl)oxy)methyl)benzofuran-4-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate The product obtained in the sixth step (905 mg) was dissolved in tetrahydrofuran (10 mL), and lithium bis(trimethylsilyl)amide (4.8 mL) was added slowly dropwise at 0° C., and the mixture was stirred at 0° C. for 30 min; the product from the fifth step (1.42 g) was dissolved in tetrahydrofuran (10 mL) and slowly added dropwise to the previous reaction mixture; the mixture was stirred at 25° C. for 3 h. LCMS showed that the reaction was completed. Saturated ammonium chloride aqueous solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, separated and purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate=3:1) to obtain the target compound (1.67 g). LCMS(ESI)[M+H]+=684.2.Step 8: Synthesis of tert-butyl (3R)-3-(1-(tert-butoxy)-3-(2-(hydroxymethyl)benzofuran-4-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0559] Tert-butyl (3R)-3-(1-(tert-butoxy)-3-(2-(((tert-butyldiphenylsilyl)oxy)methyl)benzofuran-4-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (1.67 g, 2.44 mmol, 1.0 eq) was dissolved in tetrahydrofuran (10 mL), and tetra-n-butylammonium fluoride (3.18 g, 12.2 mmol, 5.0 eq) was added at 25° C. The mixture was stirred at room temperature for 2 h. LCMS showed the reaction was completed. The mixture was filtered, and the organic phase was evaporated under reduced pressure to obtain the target compound (1.8 g). LCMS(ESI)[M+Na]+=468.4.Step 9: Synthesis of tert-butyl (3R)-3-(1-(tert-butoxy)-3-(2-formylbenzofuran-4-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0560] The product obtained in the eighth step (1.8 g, 4.04 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), and manganese dioxide (1.75 g, 20.2 mmol, 5.0 eq) was added at 25° C.; the reaction mixture was stirred at 60° C. for 2 h. LCMS showed the reaction was completed. After filtration, the organic phase was concentrated, separated and purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate=5:1) to obtain the target compound (894g). LCMS(ESI)[M+Na]+=476.4.Step 10: Synthesis of di-tert-butyl 3,3′-((((((4-(3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzofuran-2-yl)methyl)azanediyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R)-bis(pyrrolidine-1-carboxylate)

[0561] The product from the ninth step (100 mg, 0.23 mmol, 1.0 eq) was dissolved in methanol (5 mL), di-tert-butyl 3,3′-(((azanediylbis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R)-bis(pyrrolidine-1-carboxylate) (197.8 mg, 0.25 mmol, 1.1 eq) was added and stirred at 25° C. for 30 min. Sodium triacetoxyborohydride (146.2 mg, 0.69 mmol, 3.0 eq) was added and the reaction was continued for 2 h. LCMS detection showed that the reaction was completed. Water and ethyl acetate were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to obtain the target compound (65 mg). LCMS(ESI)[M+H]+=1220.1.

[0562] Step 11: Synthesis of 3,3′-(((((4-(2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzofuran-2-yl)methyl)azanediyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid) The product from the tenth step (65 mg) was dissolved in hydrochloric acid / 1,4-dioxane (1 mL) and stirred at 25° C. for 2 h. LCMS detection showed the reaction was completed. After concentration, the crude product was obtained. The target compound (4 mg) was obtained by Prep-HPLC. LCMS(ESI)[M+H]+=751.5; 1HNMR (400 MHZ, MeOD-d4) δ 7.36-7.30 (m, 3H), 7.26-7.21 (m, 4H), 7.18-7.09 (m, 4H), 6.85 (s, 1H), 3.81-3.71 (m, 2H), 3.67-3.60 (m, 4H), 3.26-2.96 (m, 14H), 2.81-2.64 (m, 5H), 2.51-2.42 (m, 2H), 2.42-2.30 (m, 3H), 2.10-2.01 (m, 3H), 1.84-1.57 (m, 3H).Example 10 (Compound 11)Preparation of (2S,2'S)-3,3′-(((((6-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzo[b]thiophen-2-yl)methyl)azanediyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)

[0563] Step 1: Synthesis of di-tert-butyl 3,3′-((2S,2'S)-(((((6-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzo[b]thiophen-2-yl)methyl)azanediyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R)-bis(pyrrolidine-1-carboxylate)

[0564] Tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(2-formylbenzo[b]thiophen-6-yl)-1-oxopropan-2-yl) pyrrolidine-1-carboxylate (86.7 mg, 0.189 mmol, 1.5 eq) was dissolved in methanol (5 mL), di-tert-butyl 3,3′-((2S,2'S)-((azanediylbis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R)-bis(pyrrolidine-1-carboxylate) (100 mg, 0.126 mmol, 1.0 eq) and sodium cyanoborohydride (15.84 mg, 0.252 mmol, 2.0 eq) were added at room temperature. The reaction mixture was stirred at room temperature for 36 h. LCMS showed that the reaction was completed. The reaction mixture was directly concentrated, separated and purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate=1:8) to obtain the target compound (90g). LCMS(ESI)[M+H]+=1235.8.Step 2: Synthesis of (2S,2'S)-3,3′-(((((6-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzo[b]thiophen-2-yl)methyl)azanediyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)

[0565] Di-tert-butyl 3,3′-((2S,2'S)-(((((6-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzo[b]thiophen-2-yl)methyl)azanediyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R)-bis(pyrrolidine-1-carboxylate) (90 mg, 0.07 mmol) was dissolved in hydrochloric acid / 1,4-dioxane (2 mL) and stirred at room temperature for 16 h. LCMS showed the reaction was completed. The reaction mixture was directly concentrated, separated and purified by preparative chromatography to obtain the target compound (32.96 mg). LCMS(ESI)[M+H]+=767.4; 1HNMR (400 MHZ, D2O) δ 7.78 (d, J=8.2 Hz, 1H), 7.70 (s, 1H), 7.43 (s, 1H), 7.30 (dd, J=18.7, 7.5 Hz, 5H), 7.17 (d, J-7.6 Hz, 2H), 7.12 (s, 2H), 4.59 (s, 2H), 4.35 (s, 4H), 3.56 (ddd, J=16.4, 11.8, 7.9 Hz, 3H), 3.43-3.34 (m, 3H), 3.27-3.16 (m, 3H), 3.08-2.90 (m, 5H), 2.86-2.69 (m, 5H), 2.64 (td, J=9.6, 5.0 Hz, 2H), 2.51 (dq, J=17.4, 8.7 Hz, 3H), 2.18-2.04 (m, 3H), 1.72 (ddd, J=18.5, 13.0, 9.2 Hz, 3H).Example 11 (Compound 49)Preparation of (2S,2'S,2″S)-3,3′,3″-((nitrilotris(methylene))tris(benzo[b]thiophene-3,5-diyl))tris(2-((R)-pyrrolidin-3-yl)propanoic acid)Step 1: Synthesis of tri-tert-butyl 3,3′,3″-((2S,2'S,2″S)-((nitrilotris(methylene))tris(benzo[b]thiophene-3,5-diyl))tris(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R,3″R)-tris(pyrrolidine-1-carboxylate)

[0566] Di-tert-butyl 3,3′-((2S,2'S)-((azanediylbis(methylene))bis(benzo[b]thiophene-3,5-diyl))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R)-bis(pyrrolidine-1-carboxylate) (40 mg, 0.04 mmol, 1.0 eq) in tetrahydrofuran (5 mL), followed by adding tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-formylbenzo[b]thiophen-5-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (22.36 mg, 0.05 mmol, 1.1 eq) and sodium cyanoborohydride (2.74 mg, 0.04 mmol, 1.0 eq). The mixture was stirred at room temperature for 16 h. LCMS showed that the reaction was completed. The reaction mixture was directly concentrated, separated and purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate=1:8) to obtain the target compound (40 mg). LCMS(ESI)[M+H]+=1347.1.Step 2: Synthesis of (2S,2'S,2″S)-3,3′,3″-((nitrilotris(methylene))tris(benzo[b]thiophene-3,5-diyl))tris(2-((R)-pyrrolidin-3-yl)propanoic acid)

[0567] Tri-tert-butyl 3,3′,3″-((2S,2'S,2″S)-((nitrilotris(methylene))tris(benzo[b]thiophene-3,5-diyl))tris(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R,3″R)-tris(pyrrolidine-1-carboxylate) (40 mg, 0.03 mmol) was dissolved in hydrochloric acid / 1,4-dioxane (2 mL) and stirred at room temperature for 16 h. LCMS showed the reaction was completed. The reaction mixture was directly concentrated, separated and purified by preparative chromatography to obtain the target compound (22.36 mg). LCMS(ESI)[M+H]+=879.0; 1HNMR (400 MHZ, D2O) 8 8.08-8.00 (m, 3H), 7.92 (d, J-8.3 Hz, 3H), 7.23 (dd, J=8.4, 1.5 Hz, 3H), 6.47 (s, 3H), 4.86 (d, J=13.7 Hz, 3H), 4.75 (s, 3H), 3.37 (ddd, J=12.0, 10.0, 5.6 Hz, 6H), 3.21-3.13 (m, 3H), 2.91 (t, J=11.0 Hz, 3H), 2.53 (ddd, J=44.9, 11.3, 5.5 Hz, 6H), 2.42-2.24 (m, 6H), 2.05 (dtd, J=13.6, 7.0, 3.3 Hz, 3H), 1.65 (dq, J=13.2, 9.7 Hz, 3H).Example 12 (Compound 65)Preparation of (2S,2'S,2″S)-3,3′,3″-((nitrilotris (ethane-2,1-diyl))tris (benzene-3,1-diyl))tris(2-((R)-pyrrolidin-3-yl)propanoic acid)Step 1: Synthesis of tert-butyl (R)-3-((S)-3-(3-allylphenyl)-1-(tert-butoxy)-1-oxopropan-2-yl) pyrrolidine-1-carboxylate

[0568] Tert-butyl (R)-3-((S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (1500 mg, 3.3 mmol, 1.0 eq) was dissolved in 1,4-dioxane (20 mL), followed by adding 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.11 g, 6.6 mmol, 2 eq) and potassium phosphate (2.1 g, 9.9 mmol, 3 eq), and then water (4 mL); the mixture was stirred at 90° C. for 16 h under nitrogen. LCMS showed that the reaction was completed. The reaction mixture was directly concentrated, separated and purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate=2:1) to obtain the target compound (900 mg). LCMS(ESI)[M+H]+=416.3.Step 2: Synthesis of tert-butyl (R)-3-((S)-1-(tert-butoxy)-1-oxo-3-(3-(2-oxoethyl)phenyl)propan-2-yl)pyrrolidine-1-carboxylate

[0569] Tert-butyl (R)-3-((S)-3-(3-allylphenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (900 mg, 2.17 mmol, 1.0 eq) was dissolved in 1,4-dioxane (20 mL), and sodium periodate (1.85 g, 8.66 mmol, 4 eq) and potassium osmate dihydrate (80 mg, 0.22 mmol, 0.1 eq) were added, which were stirred at room temperature for 16 h. LCMS showed that the reaction was completed. The reaction mixture was directly concentrated, separated and purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate=1:1) to obtain the target compound (600 mg). LCMS(ESI)[M+H]+=418.3.Step 3: Synthesis of di-tert-butyl 3,3′-((2S,2'S)-((azanediylbis(ethane-2,1-diyl))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R)-bis(pyrrolidine-1-carboxylate)

[0570] Tert-butyl (R)-3-((S)-1-(tert-butoxy)-1-oxo-3-(3-(2-oxoethyl)phenyl)propan-2-yl)pyrrolidine-1-carboxylate (400 mg, 0.96 mmol, 1.0 eq) was dissolved in methanol (10 mL), ammonia / methanol (16.31 mg, 0.96 mmol, 1.0 eq), two drops of acetic acid and sodium cyanoborohydride (71 mg, 1.15 mmol, 1.2 eq) were added, and the mixture was stirred at room temperature for 16 h. LCMS showed that the reaction was completed. The reaction mixture was directly concentrated, separated and purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate=1:8) to obtain the target compound (100 mg). LCMS(ESI)[M+H]+=820.6.

[0571] Step 4: Synthesis of tri-tert-butyl 3,3′,3″-((2S,2'S,2″S)-((nitrilotris (ethane-2,1-diyl))tris (benzene-3,1-diyl))tris(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R,3″R)-tris(pyrrolidine-1-carboxylate) Di-tert-butyl 3,3′-((2S,2'S)-((azanediylbis(ethane-2,1-diyl))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R)-bis(pyrrolidine-1-carboxylate) (100 mg, 0.12 mmol, 1.0 eq) was dissolved in methanol (5 mL), followed by adding tert-butyl (R)-3-((S)-1-(tert-butoxy)-1-oxo-3-(3-(2-oxoethyl)phenyl)propan-2-yl)pyrrolidine-1-carboxylate (51 mg, 0.12 mmol, 1.0 eq), two drops of acetic acid, and sodium cyanoborohydride (7.5 mg, 0.12 mmol, 1.0 eq). The mixture was stirred at room temperature for 16 h. LCMS showed that the reaction was completed. The reaction mixture was directly concentrated, separated and purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate=1:8) to obtain the target compound (80 mg). LCMS(ESI)[M+H]+=1221.9.Step 5: Synthesis of (2S,2'S,2″S)-3,3′,3″-((nitrilotris (ethane-2,1-diyl))tris (benzene-3,1-diyl))tris(2-((R)-pyrrolidin-3-yl)propanoic acid)

[0572] Tri-tert-butyl 3,3′,3″-((2S,2'S,2″S)-((nitrilotris (ethane-2,1-diyl))tris (benzene-3,1-diyl))tris(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R,3″R)-tris(pyrrolidine-1-carboxylate) (80 mg) was dissolved in hydrochloric acid / 1,4-dioxane (2 mL) and stirred at room temperature for 16 h. LCMS showed the reaction was completed. The reaction mixture was directly concentrated, separated and purified by preparative chromatography to obtain the target compound (9.7 mg). LCMS(ESI)[M+H]+=753.7; 1HNMR (400 MHZ, D2O) δ 7.21 (t, J=7.5 Hz, 3H), 7.09-6.99 (m, 9H), 3.40-3.30 (m, 6H), 3.14 (ddd, J=11.7, 9.9, 7.3 Hz, 4H), 2.96 (d, J=7.5 Hz, 4H), 2.85 (dd, J=11.7, 9.2 Hz, 4H), 2.78 (d, J-9.1 Hz, 7H), 2.72-2.64 (m, 5H), 2.39 (dq, J=14.9, 9.1, 6.8 Hz, 6H), 2.04 (td, J-6.5, 3.6 Hz, 3H), 1.71-1.63 (m, 3H).Example 13 (Compound 67)Preparation of (2S,2'S,2″S)-3,3′,3″-((nitrilotris (ethane-2,1-diyl))tris (benzofuran-3,5-diyl))tris(2-((R)-pyrrolidin-3-yl)propanoic acid)Step 1: Synthesis of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-((E)-2-(hydroxyimino)ethyl)benzofuran-5-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0573] Tert-butyl (R)-3-((S)-1-(tert-butoxy)-1-oxo-3-(3-(2-oxoethyl)benzofuran-5-yl)propan-2-yl) pyrrolidine-1-carboxylate (120 mg, 0.26 mmol, 1.0 eq) was dissolved in ethanol (10 mL), and hydroxylamine hydrochloride (37 mg, 0.52 mmol, 2.0 eq) was added; the mixture was stirred at room temperature for 16 h; LCMS showed the reaction was completed. The reaction mixture was filtered, and the filtrate was concentrated, separated and purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate=1:8) to obtain the target compound (100 mg). LCMS(ESI)[M+H]+=473.2.Step 2: Synthesis of tert-butyl (R)-3-((S)-3-(3-(2-aminoethyl)benzofuran-5-yl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0574] Tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-((E)-2-(hydroxyimino)ethyl)benzofuran-5-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (100 mg, 0.21 mmol, 1.0 eq) was dissolved in methanol (10 mL), and Pd / C (10 mg) was added; the mixture was stirred at room temperature for 16 h under a hydrogen. LCMS showed the reaction was completed. The reaction mixture was filtered and evaporated under reduced pressure. The residue was separated and purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate=1:8) to obtain the target compound (70 mg). LCMS(ESI)[M+H]+=459.2.

[0575] Step 3: Synthesis of tri-tert-butyl 3,3′,3″-((2S,2'S,2″S)-((nitrilotris (ethane-2,1-diyl))tris (benzofuran-3,5-diyl))tris(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R,3″R)-tris(pyrrolidine-1-carboxylate) Tert-butyl (R)-3-((S)-3-(3-(2-aminoethyl)benzofuran-5-yl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (100 mg, 0.22 mmol, 1.0 eq) was dissolved in methanol (10 mL), followed by adding tert-butyl (R)-3-((S)-1-(tert-butoxy)-1-oxo-3-(3-(2-oxoethyl)benzofuran-5-yl)propan-2-yl) pyrrolidine-1-carboxylate (200 mg, 0.44 mmol, 2.0 eq) and sodium cyanoborohydride (27 mg, 0.44 mmol, 2.0 eq); the mixture was stirred at room temperature for 16 h. LCMS showed the reaction was completed. The reaction mixture was concentrated after cooling and separated and purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate=1:1) to obtain the target compound (100 mg).Step 4: Synthesis of (2S,2'S,2″S)-3,3′,3″-((nitrilotris (ethane-2,1-diyl))tris (benzofuran-3,5-diyl))tris(2-((R)-pyrrolidin-3-yl)propanoic acid)

[0576] Tri-tert-butyl 3,3′,3″-((2S,2'S,2″S)-((nitrilotris (ethane-2,1-diyl))tris (benzofuran-3,5-diyl))tris(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R,3″R)-tris(pyrrolidine-1-carboxylate) (100 mg, 0.07 mmol) was dissolved in hydrochloric acid / 1,4-dioxane (4 mL) and stirred at room temperature for 16 h. LCMS showed the reaction was completed. The reaction mixture was directly concentrated, separated and purified by preparative chromatography to obtain the target compound (6.58 mg). LCMS(ESI)[M+H]+=873.2; 1HNMR (400 MHz, D2O) δ 7.26-7.14 (m, 6H), 6.94 (s, 6H), 3.17 (d, J=33.2 Hz, 4H), 2.95 (d, J=26.8 Hz, 5H), 2.61 (d, J=51.5 Hz, 22H), 2.41-2.10 (m, 7H), 1.73 (dd, J=101.8, 31.7 Hz, 3H), 1.08 (s, 1H).Example 14 (Compound 71)Preparation of (2S,2'S)-3,3′-((((2-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenoxy)ethyl) azanediyl)bis(ethane-2,1-diyl))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)Step 1: Synthesis of tert-butyl (R)-3-((S)-1-(tert-butoxy)-1-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)pyrrolidine-1-carboxylate

[0577] Tert-butyl (R)-3-((S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (1.5 g) was dissolved in 1,4-dioxane (20 mL), followed by adding bis(pinacolato)diboron (1.75 g), [1,1′-bis(diphenylphosphino) ferrocene]palladium (II) dichloride (241.4 mg) and potassium acetate (972 mg), and water (4 mL); the mixture was stirred at 90° C. for 16 h under nitrogen. LCMS showed that the reaction was completed. The reaction mixture was directly concentrated, separated and purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate=2:1) to obtain the target compound (1.2 g). LCMS(ESI)[M+H-Boc]+=402.2.Step 2: Synthesis of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-hydroxyphenyl)-1-oxopropan-2-yl) pyrrolidine-1-carboxylate

[0578] Tert-butyl (R)-3-((S)-1-(tert-butoxy)-1-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)pyrrolidine-1-carboxylate (1200 mg) was dissolved in tetrahydrofuran (20 mL), followed by adding hydrogen peroxide (0.5 mL). The mixture was stirred at room temperature for 16 h. LCMS showed that the reaction was completed. The reaction mixture was directly concentrated, separated and purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate=1:1) to obtain the target compound (800 mg). LCMS(ESI)[M−2×tert-butyl]+=280.Step 3: Synthesis of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-(2-(1,3-dioxoisoindolin-2-yl) ethoxy)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0579] Tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-hydroxyphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (500 mg) was dissolved in N,N-dimethylformamide (5 mL), followed by adding 2-(2-bromoethyl) isoindoline-1,3-dione (649 mg) and potassium carbonate (530 mg). The mixture was stirred at 90° C. for 2 h. LCMS showed that the reaction was completed. The reaction mixture was directly concentrated, separated and purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate=1:1) to obtain the target compound (280 mg). LCMS(ESI)[M+H]+=565.3.Step 4: Synthesis of tert-butyl (R)-3-((S)-3-(3-(2-aminoethoxy)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0580] Tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-(2-(1,3-dioxoisoindolin-2-yl) ethoxy)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (280 mg) was dissolved in ethanol (10 mL) and hydrazine hydrate (124 mg) was added. The mixture was stirred at 90° C. for 16 h. LCMS showed that the reaction was completed. The reaction mixture was directly concentrated, separated and purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate=1:5) to obtain the target compound (160 mg). LCMS(ESI)[M+H]+=435.3.

[0581] Step 5: Synthesis of di-tert-butyl 3,3′-((2S,2'S)-((((2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenoxy)ethyl) azanediyl)bis(ethane-2,1-diyl))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R)-bis(pyrrolidine-1-carboxylate) Tert-butyl (R)-3-((S)-3-(3-(2-aminoethoxy)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (80 mg) was dissolved in methanol (10 mL), followed by adding tert-butyl (R)-3-((S)-1-(tert-butoxy)-1-oxo-3-(3-(2-oxoethyl)phenyl)propan-2-yl)pyrrolidine-1-carboxylate (154 mg) and sodium cyanoborohydride (23 mg). The mixture was stirred at room temperature for 16 h. LCMS showed that the reaction was completed. The reaction mixture was directly concentrated, separated and purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate=1:8) to obtain the target compound (100 mg). LCMS(ESI)[M+H]+=1237.9.Step 6: Synthesis of (2S,2'S)-3,3′-((((2-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenoxy)ethyl) azanediyl)bis(ethane-2,1-diyl))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)

[0582] Di-tert-butyl 3,3′-((2S,2'S)-((((2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenoxy)ethyl) azanediyl)bis(ethane-2,1-diyl))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R)-bis(pyrrolidine-1-carboxylate) (100 mg) was dissolved in hydrochloric acid / 1,4-dioxane (2 mL) and stirred at room temperature for 16 h. LCMS showed the reaction was completed. The reaction mixture was directly concentrated, separated and purified by preparative chromatography to obtain the target compound (27.9 mg). LCMS(ESI)[M+H]+=769.5; 1HNMR (400 MHZ, D2O) δ 7.24-7.09 (m, 4H), 7.00 (q, J=8.0 Hz, 5H), 6.82 (d, J-7.4 Hz, 1H), 6.73 (d, J=8.3 Hz, 2H), 4.17-4.06 (m, 2H), 3.39-3.28 (m, 6H), 3.17-3.03 (m, 5H), 2.90 (d, J=9.4 Hz, 3H), 2.86-2.58 (m, 14H), 2.37 (td, J=17.0, 15.4, 6.6 Hz, 6H), 2.02 (s, 3H), 1.66 (dd, J=14.2, 6.5 Hz, 3H).Example 15 (Compound 80)Preparation of (2S,2'S)-3,3′-((2,2′-((2-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenoxy)ethyl) azanediyl)bis(acetyl))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)Step 1: Synthesis of (3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl) boronic acid

[0583] Tert-butyl (R)-3-((S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (1900 mg, 4.18 mmol, 1 eq), (dihydroxyboranyl) boronic acid (562.29 mg, 6.27 mmol, 1.5 eq), potassium acetate (1230.7 mg, 12.54 mmol, 3 eq), dicyclohexyl [2′,4′,6′-tri (propan-2-yl)-[1,1′-biphenyl]-2-yl]phosphine (199.27 mg, 0.42 mmol, 0.1 eq) and XPhos Pd G2 (164 mg, 0.21 mmol, 0.05 eq) were added in ethanol (20 mL). The reaction mixture was purged with nitrogen three times and stirred at 90° C. for 16 h. LCMS showed the reaction was completed. After the addition of ethyl acetate, the mixture was filtered through diatomaceous earth. The filtrate was evaporated under reduced pressure to obtain the target compound (2000 mg), which was used in the next step directly.Step 2: Synthesis of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-hydroxyphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0584] (3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl) boronic acid (2000 mg, 4.77 mmol, 1 eq) was dissolved in tetrahydrofuran (30 mL) and hydrogen peroxide (8 mL) was added. The mixture was stirred at 20° C. for 16 h; LCMS detection showed that the reaction was completed, saturated sodium bisulfite solution and ethyl acetate were added, and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=4:1) to obtain the target compound (800 mg). LCMS(ESI)[M+H]+=392.2.Step 3: Synthesis of tert-butyl (R)-3-((S)-3-(3-(2-(((benzyloxy) carbonyl)amino)ethoxy)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0585] Tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-hydroxyphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (2 g, 5.11 mmol, 1 eq), benzyl(2-bromoethyl) carbamate (2.64 g, 10.22 mmol, 2 eq) and potassium carbonate (2.12 g, 15.33 mmol, 3 eq) were added in acetonitrile (50 mL) and stirred at 90° C. for 16 h; LCMS showed the reaction was completed. The reaction mixture was directly purified by column chromatography (petroleum ether:ethyl acetate=7:1) to obtain the target compound (3g). LCMS(ESI)[M+H]+=569.0.Step 4: Synthesis of tert-butyl (R)-3-((S)-3-(3-(2-aminoethoxy)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0586] Tert-butyl (R)-3-((S)-3-(3-(2-(((benzyloxy) carbonyl)amino)ethoxy)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (3 g, 5.27 mmol, 1 eq) was dissolved in methanol (50 mL), palladium (300 mg, 10%) was added, and the mixture was exchanged with hydrogen three times; the mixture was stirred at 25° C. for 16 h. LCMS detection showed that the reaction was completed. The reaction mixture was filtered, and the filtrate was concentrated to obtain the target compound (2g). LCMS(ESI)[M+H]+=435.4Step 5: Synthesis of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-(2-chloroacetyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0587] Tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-(methoxycarbonyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (700 mg, 1.614 mmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (10 mL) and cooled to −78° C. Lithium diisopropylamide (1.0M, 2.42 mL, 2.42 mmol, 1.5 eq) was added to the mixture and stirred at −78° C. for 1 h. Chloroiodomethane (854.03 mg, 4.84 mmol, 3 eq) was added to the mixture and stirred at −78° C. for another 2 h. LCMS detection showed that the reaction was completed. Saturated ammonium chloride aqueous solution and ethyl acetate were added to the reaction mixture and the reaction mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=4:1) to obtain the target compound (100 mg). LCMS(ESI)[M+H-Boc]+=352.4.Step 6: Synthesis of di-tert-butyl 3,3′-((2S,2'S)-((2,2′-((2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenoxy)ethyl) azanediyl)bis(acetyl))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R)-bis(pyrrolidine-1-carboxylate)

[0588] Tert-butyl (R)-3-((S)-3-(3-(2-aminoethoxy)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (192.2 mg, 0.44 mmol, 2 eq) and tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-(2-chloroacetyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (100 mg, 0.22 mmol, 1 eq) were dissolved in acetonitrile (3 mL), anhydrous potassium carbonate (91.1 mg, 0.66 mmol, 3 eq) was added, and the mixture was stirred at 60° C. for 2 h; LCMS detection showed that the reaction was completed. The reaction mixture was directly concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to obtain the target compound (50 mg). LCMS(ESI)[M+H]+=1265.3.Step 7: Synthesis of (2S,2'S)-3,3′-((2,2′-((2-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenoxy)ethyl) azanediyl)bis(acetyl))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)

[0589] Di-tert-butyl 3,3′-((2S,2'S)-((2,2′-((2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenoxy)ethyl) azanediyl)bis(acetyl))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R)-bis(pyrrolidine-1-carboxylate) (50 mg, 0.04 mmol, 1 eq) was added in hydrochloric acid / 1,4-dioxane (2 mL, 4.0M) at 0° C., the mixture was stirred at 25° C. for 6 h; LCMS showed the reaction was completed. The reaction mixture was concentrated to obtain a crude product, which was purified by Prep-HPLC to obtain the target compound (6 mg). LCMS(ESI)[M−H]−=795.6; 1HNMR (400 MHZ, DMSO) δ7.90 (s, 2H), 7.81 (d, J-8.0 Hz, 2H), 7.63 (d, J=7.6 Hz, 2H), 7.53 (d, J=8.0 Hz, 2H), 7.10 (t, J=8.0 Hz, 1H), 6.76 (d, J-7.6 Hz, 1H), 6.53-6.45 (m, 2H), 5.34 (s, 3H), 4.46 (s, 2H), 3.92 (s, 2H), 3.34-2.69 (m, 25H), 2.41-2.32 (m, 3H), 2.03-1.95 (m, 3H), 1.69-1.62 (m, 3H).Example 16 (Compound 81)Preparation of (2S,2'S)-3,3′-((((2-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenoxy)acetyl)azanediyl)bis(ethane-2,1-diyl))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)Step 1: Synthesis of di-tert-butyl 3,3′-((2S,2'S)-((azanediylbis(ethane-2,1-diyl))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R)-bis(pyrrolidine-1-carboxylate))

[0590] Tert-butyl (R)-3-((S)-3-(3-(2-aminoethyl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (100 mg) was dissolved in methanol (10 mL), followed by adding tert-butyl (R)-3-((S)-1-(tert-butoxy)-1-oxo-3-(3-(2-oxoethyl)phenyl)propan-2-yl)pyrrolidine-1-carboxylate (100 mg) and sodium cyanoborohydride (15 mg). The mixture was stirred at room temperature for 16 h. LCMS showed the reaction was completed. The reaction mixture was concentrated after cooling and separated and purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate=1:1) to obtain the target compound (100 mg). LCMS(ESI)[M+H]+=820.6.Step 2: Synthesis of di-tert-butyl 3,3′-((2S,2'S)-((((2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenoxy)acetyl)azanediyl)bis(ethane-2,1-diyl))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R)-bis(pyrrolidine-1-carboxylate)

[0591] Di-tert-butyl 3,3′-((2S,2'S)-((azanediylbis(ethane-2,1-diyl))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R)-bis(pyrrolidine-1-carboxylate) (10 mL) was added in 2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenoxy) acetic acid (82 mg), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (93 mg) and N,N-diisopropylethylamine (47 mg); The mixture was stirred at room temperature for 16 h. LCMS showed the reaction was completed. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried, filtered, and concentrated to obtain a crude product, which was separated and purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate=1:8) to obtain the target compound (70 mg). LCMS(ESI)[M+H-Boc]+=1152.0.Step 3: Synthesis of (2S,2'S)-3,3′-((((2-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenoxy)acetyl)azanediyl)bis(ethane-2,1-diyl))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)

[0592] Di-tert-butyl 3,3′-((2S,2'S)-((((2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenoxy)acetyl)azanediyl)bis(ethane-2,1-diyl))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R)-bis(pyrrolidine-1-carboxylate)) (70 mg) was dissolved in hydrochloric acid / 1,4-dioxane (4 mL) and stirred at room temperature for 16 h. LCMS showed the reaction was completed. The reaction mixture was directly concentrated, separated and purified by preparative chromatography to obtain the target compound (13.41 mg). LCMS(ESI)[M+H]+=783.1; 1HNMR (400 MHZ, D2O) δ 7.21 (td, J=7.7, 2.0 Hz, 2H), 7.14-6.99 (m, 7H), 6.80 (d, J-7.6 Hz, 1H), 6.57 (t, J=2.1 Hz, 1H), 6.08 (dd, J=8.2, 2.6 Hz, 1H), 4.14-4.04 (m, 2H), 3.63-3.55 (m, 2H), 3.41-3.26 (m, 7H), 3.14 (dddd, J-25.2, 23.0, 11.2, 4.0 Hz, 4H), 2.87-2.63 (m, 12H), 2.60-2.54 (m, 1H), 2.43-2.25 (m, 6H), 2.10-1.98 (m, 3H), 1.66 (td, J=12.8, 11.1, 7.5 Hz, 3H).Example 17 (Compound 90)Preparation of (2S,2'S,2″S)-3,3′,3″-((nitrilotris(methylene-d2))tris(benzene-3,1-diyl))tris(2-((R)-pyrrolidin-3-yl)propanoic acid)Step 1: Synthesis of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-(hydroxymethyl-d2)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0593] Tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-(methoxycarbonyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (1.2 g, 2.77 mmol, 1 eq) was dissolved in a mixture of tetrahydrofuran (14.4 mL) and deuterated methanol (4.2 mL) and deuterated sodium borohydride (695.19 mg, 16.61 mmol, 6 eq) was added batchwise under nitrogen. The reaction mixture was stirred at 70° C. for 3 h. LCMS showed the reaction was completed. The reaction mixture was cooled to room temperature, followed by addition of deuterium oxide (5 mL). The reaction mixture was stirred for 10 min. Water and ethyl acetate were added to the reaction mixture and the mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=2:1) to obtain the target compound (600 mg). LCMS(ESI)[M+Na]+=430.2.Step 2: Synthesis of tert-butyl (R)-3-((S)-3-(3-(bromomethyl-d2)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0594] Tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-(hydroxymethyl-d2)phenyl)-1-oxopropan-2-yl) pyrrolidine-1-carboxylate (600 mg, 1.47 mmol, 1 eq) was dissolved in dichloromethane (5 mL) and cooled to 0° C. Triphenylphosphine (1158.47 mg, 4.42 mmol, 3 eq) and N-bromosuccinimide (786.09 mg, 4.42 mmol, 3 eq) were added. The mixture was stirred at room temperature for 2 h. LCMS detection showed that the reaction was completed. Water and dichloromethane were added, and the reaction mixture was extracted. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate=3:1) to obtain the target compound (400 mg). LCMS(ESI)[M+Na]+=492.7.Step 3: Synthesis of tri-tert-butyl 3,3′,3″-((2S,2'S,2″S)-((nitrilotris(methylene-d2))tris(benzene-3,1-diyl))tris(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R,3″R)-tris(pyrrolidine-1-carboxylate)

[0595] Tert-butyl (R)-3-((S)-3-(3-(aminomethyl-d2)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (30 mg, 0.07 mmol, 1 eq), tert-butyl (R)-3-((S)-3-(3-(bromomethyl-d2)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (69.43 mg, 0.15 mmol, 2 eq) and potassium carbonate (30.6 mg, 0.22 mmol, 3 eq) were added in acetonitrile (1 mL), heated to 60° C. and stirred for 4 h. LCMS detection showed that the reaction was completed and the reaction mixture was filtered. The filtrate was directly purified by silica gel column chromatography (petroleum ether / ethyl acetate=3:1) to obtain the target compound (55 mg). LCMS(ESI)[M+H]+=1185.8.Step 4: Synthesis of (2S,2'S,2″S)-3,3′,3″-((nitrilotris(methylene-d2))tris(benzene-3,1-diyl))tris(2-((R)-pyrrolidin-3-yl)propanoic acid)

[0596] Tri-tert-butyl 3,3′,3″-((2S,2'S,2″S)-((nitrilotris(methylene-d2))tris(benzene-3,1-diyl))tris(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3′R,3″R)-tris(pyrrolidine-1-carboxylate) (50 mg, 0.04 mmol, 1 eq) was added in hydrochloric acid / 1,4-dioxane (3.0 mL, 4M) and stirred at 25° C. for 2 h. LCMS detection showed that the reaction was completed and the reaction mixture was filtered. The filter cake was lyophilized with acetonitrile and water to obtain the target compound (25.84 mg). LCMS(ESI)[M-H]−=715.5; 1HNMR (400 MHz, D2O) δ 7.38-7.27 (m, 6H), 7.1-7.11 (m, 6H), 3.61-3.51 (m, 3H), 3.38-3.33 (m, 3H), 3.28-3.16 (m, 3H), 3.07-2.98 (m, 3H), 2.91-2.87 (m, 3H), 2.84-2.74 (m, 3H), 2.68-2.58 (m, 3H), 2.53-2.47 (m, 3H), 2.15-2.09 (m, 3H), 1.78-1.65 (m, 3H).Example 18 (Compound 91)Preparation of (2S,2'S,2″S)-3,3′,3″-((nitrilotris(methylene))tris(benzene-3,1-diyl))tris(2-((R)-pyrrolidin-3-yl)propanoic-3,3-d2 acid)Step 1: Synthesis of tert-butyl (R)-3-((S)-1-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(3-bromophenyl)-1-oxopropan-2-yl-3,3-d2) pyrrolidine-1-carboxylate

[0597] Under ice bath and nitrogen, a solution of lithium bis(trimethylsilyl)amide (7.08 mL, 7.08 mmol, 1.1 eq, 1.0M) was added dropwise to a solution of tert-butyl (R)-3-(2-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl) pyrrolidine-1-carboxylate (2.5 g, 6.44 mmol, 1 eq) in tetrahydrofuran (30 mL). The mixture was stirred at 0° C. for 30 min; a solution of 1-bromo-3-(chloromethyl-d2)benzene (1.47 g, 7.08 mmol, 1.1 eq) in tetrahydrofuran (2 mL) was slowly added dropwise, and after the addition, the reaction temperature was slowly raised to room temperature and the mixture was stirred for 16 h. LCMS showed the reaction was completed, the reaction mixture was cooled with an ice-water bath, saturated aqueous ammonium chloride solution and water were added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain the target compound (3.1 g). LCMS(ESI)[M+H-tert-butyl]+=503.2.Step 2: Synthesis of(S)-3-(3-bromophenyl)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)propanoic-3,3-d2 acid

[0598] A solution of hydrogen peroxide (275 mg, 8.1 mmol, 1.5 eq) was added to a solution of tert-butyl (R)-3-((S)-1-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(3-bromophenyl)-1-oxopropan-2-yl-3,3-d2) pyrrolidine-1-carboxylate (3 g, 5.28 mmol, 1 eq) in tetrahydrofuran (120 mL) and cooled with an ice bath, followed by adding a solution (10 mL) of lithium hydroxide (192 mg, 8.1 mmol, 1.5 eq). The reaction mixture was stirred at 25° C. for 2.5 h. LCMS showed the reaction was completed, the reaction mixture was cooled to 0° C., and a solution (5 mL) of sodium bisulfite (1 g) and sodium hydroxide solution (5N) were added to adjust the pH of the reaction mixture to >12. The mixture was extracted with water and methyl tert-butyl ether, and the organic phase was discarded. The aqueous phase was acidified to pH3 with hydrochloric acid solution (5N) and extracted with methyl tert-butyl ether. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target compound (1.8 g). LCMS(ESI)[M+H-Boc]+=300.20.Step 3: Synthesis of tert-butyl (R)-3-((S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl-3,3-d2) pyrrolidine-1-carboxylate

[0599] (S)-3-(3-bromophenyl)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)propanoic-3,3-d2 acid (1.8 g, 4.5 mmol, 1 eq) was dissolved in 2-methyltetrahydrofuran (50 mL), tert-butyl N,N′-diisopropylcarbamimidate (4.5 g, 22.5 mmol, 5 eq) was added, and the mixture was heated to 65° C. and stirred for 16 h under nitrogen, LCMS showed the reaction was completed, the insoluble matter was filtered, the filter cake was washed with methyl tert-butyl ether, and the filtrate was concentrated to obtain a crude product. The crude product was separated and purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate=10:1) to obtain the target compound (0.6 g). LCMS(ESI)[M+H-2×tert-butyl]+=344.16.Step 4: Synthesis of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-formylphenyl)-1-oxopropan-2-yl-3,3-d2) pyrrolidine-1-carboxylate

[0600] Tert-butyl (R)-3-((S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl-3,3-d2) pyrrolidine-1-carboxylate (0.6 g, 1.31 mmol, 1 eq) was dissolved in N,N-dimethylformamide (4 mL), followed by adding palladium acetate (59 mg, 0.26 mmol, 0.2 eq), 1,4-bis(diphenylphosphino) butane (112 mg, 0.26 mmol, 0.2 eq), N-formylsaccharin (691 mg, 3.296 mmol, 2.5 eq), sodium carbonate (418 mg, 3.94 mmol, 3 eq) and triethylsilane (305 mg, 2.63 mmol, 2 eq); under nitrogen, the mixture was heated to 75° C. and stirred for 16 h. The LCMS showed the reaction was completed. The insoluble matter was filtered, the filter cake was washed with methyl tert-butyl ether. The filtrate was concentrated, separated and purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate=10:1) to obtain the target compound (165 mg). LCMS(ESI)[M+H-Boc]+=306.35.Step 5: Synthesis of tri-tert-butyl 3,3′,3″-((2S,2'S,2″S)-((nitrilotris(methylene))tris(benzene-3,1-diyl))tris(3-(tert-butoxy)-3-oxopropane-1,2-diyl-1,1-d2)) (3R,3′R,3″R)-tris(pyrrolidine-1-carboxylate)

[0601] Tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-formylphenyl)-1-oxopropan-2-yl-3,3-d2) pyrrolidine-1-carboxylate (160 mg, 0.39 mmol, 1 eq) was dissolved in tetrahydrofuran (5 mL), to which ammonia methanol (0.018 mL, 0.13 mmol, 0.33 eq, 7.0M), sodium cyanoborohydride (61 mg, 0.97 mmol, 2.5 eq) and one drop of acetic acid were added. The reaction mixture was stirred at room temperature overnight. LCMS showed the reaction was completed. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain the product (40 mg). LCMS(ESI)[M+H]+=1186.02.Step 6: Synthesis of (2S,2'S,2″S)-3,3′,3″-((nitrilotris(methylene))tris(benzene-3,1-diyl))tris(2-((R)-pyrrolidin-3-yl)propanoic-3,3-d2 acid)

[0602] Tri-tert-butyl 3,3′,3″-((2S,2'S,2″S)-((nitrilotris(methylene))tris(benzene-3,1-diyl))tris(3-(tert-butoxy)-3-oxopropane-1,2-diyl-1,1-d2)) (3R,3′R,3″R)-tris(pyrrolidine-1-carboxylate) (30 mg, 0.03 mmol, 1 eq) was dissolved in 1,4-dioxane (1 mL), and hydrochloric acid / 1,4-dioxane (1 mL, 4.0M) was added; the mixture was stirred at room temperature overnight, and the reaction was monitored by LCMS until completion. The solvent was evaporated under reduced pressure, and the residue was separated and purified by Prep-HPLC (C18, 10 mmol / L NH4HCO3 in water, MeCN) to obtain the target compound (4.5 mg). LCMS(ESI)[M+H]+=717.63; 1HNMR (400 MHZ, D2O) δ 8.37 (s, 2H), 7.40-7.25 (m, 6H), 7.24-7.09 (m, 6H), 4.19 (s, 6H), 3.56-3.43 (m, 3H), 3.40-3.29 (m, 3H), 3.26-3.13 (m, 3H), 3.00-2.87 (m, 3H), 2.49-2.30 (m, 6H), 2.15-1.97 (m, 3H), 1.75-1.59 (m, 3H).Example 19 (Compound 93)Preparation of (2S,2'S)-3,3′-((((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl) azanediyl)bis(methylene-d2))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)Step 1: Synthesis of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-(hydroxymethyl-d2)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0603] Tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-(methoxycarbonyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (1.2 g, 2.77 mmol, 1 eq) was dissolved in a mixture of tetrahydrofuran (14.4 mL) and deuterated methanol (4.2 mL) and deuterated sodium borohydride (695.19 mg, 16.61 mmol, 6 eq) was added batchwise under nitrogen; the reaction mixture was stirred at 70° C. for 3 h. LCMS showed the reaction was completed. The...

Claims

1. -19. (canceled)20. A compound which is:or a pharmaceutically acceptable salt thereof.

21. A compound of claim 20, which is:

22. The pharmaceutically acceptable salt of claim 20, which is a pharmaceutically acceptable salt of:

23. A pharmaceutical composition comprising the compound of claim 20, or a pharmaceutically acceptable salt thereof.

24. The pharmaceutical composition of claim 23, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

25. A method of preventing and / or treating diseases or conditions associated with elevated blood plasma Lp(a) levels, which method comprises administering a therapeutically effective amount of the compound of claim 20, or a pharmaceutically acceptable salt thereof.

26. The method of claim 25, wherein the disease or condition associated with elevated blood plasma Lp(a) levels is a cardiovascular disease (CVD).

27. The method of claim 26, wherein the cardiovascular disease (CVD) is selected from the group consisting of: atherosclerotic cardiovascular disease (ASCVD), coronary artery stenosis, aortic valve stenosis, heart failure, and atrial fibrillation.

28. The method of claim 27, wherein the atherosclerotic cardiovascular disease (ASCVD) is selected from the group consisting of: peripheral vascular disease, coronary heart disease, and ischemic stroke.

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